1. Candidate genes for ADHD with a plausible mechanism of action on ADHD

• ADHD candidate genes with a plausible mechanism of action related to ADHD
• Dopamine
  • Dopamine synthesis
    • 1.8. DDC, AADC, Aromatic L-Amino Acid Decarboxylase (Chromosome 9q34.2)
    • 1.9. TH, Tyrosine Hydroxylase (Chromosome 11p15.5)
    • 1.121. AS3MT, Arsenite Methyltransferase
    • FAH, fumarylacetoacetate hydrolase
    • GCH1
  • Dopamine Storage and Release
    • 1.28. SNAP25, Synaptosome-Associated Protein 25 (Chromosome 20p12.3; T1065G)
    • 1.275. SYT1, Synaptotagmin 1
    • 2.99. DNM1, Dynamin 1
  • Dopamine Effects
    • 1.1. DRD1, dopamine receptor D1 (chromosome 5q35.2)
    • 1.2. DRD2, dopamine receptor D2 (chromosome 11q23.1; TAQ1A, rs1800497)
    • 1.3. DRD3, dopamine receptor D3 (chromosome 3q13.31)
    • 1.4. DRD4, dopamine receptor D4 (chromosome 11p15.5, exon III, VTNR) (x)
    • 1.5. DRD5, dopamine receptor D5 (chromosome 4p16.1-p15.3; CARepeat, 148 bp)
    • 1.234. ADORA2A, ADENOSINE A2A RECEPTOR
    • 1.109. PPP2R2B, Protein Phosphatase 2 Regulatory Subunit B beta
    • SORCS2
  • Dopamine degradation
    • Dopamine reuptake
      • 1.6. SLC6A3, DAT1, dopamine transporter gene (chromosome 5p15.3; 10-R allele, VNTR)
      • 1.18. SLC6A2, NET, norepinephrine transporter gene (chromosome 16q12.2)
      • 1.97. CACNA1C, Calcium Voltage-Gated Channel Subunit Alpha1 C
      • 1.98. CACNB2, Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2
      • 1.105. MAN2A2, Alpha Mannosidase Class 2A Member 2
      • 2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A
      • 1.93. TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD
      • 1.366 Transferrin gene
    • Dopamine Metabolism
      • 1.10. MAOA, Monoamine Oxidase A Gene (Chromosome Xp11.3) (x)
      • 1.11. MAOB, Monoamine Oxidase B Gene (Chromosome Xp11.4-p11.3)
      • 1.12. COMT, Catechol-O-Methyltransferase (Chromosome 22q11.21)
        • 1.12.1. COMT Val158Val
        • 1.12.2. COMT Met158Met
        • 1.12.3. COMT Val108/158 Met
      • 1.283. STS, STEROID SULFATASE
  • Dopamine Regulation
    • 1.31. DRD1IP, Calcylon (Chromosome 10q26) (x)
    • 1.78. MTHFR, 5,10-Methylenetetrahydrofolate Reductase
    • 1.81. ARTN, Artemin; 1p34.1
    • 1.127. GPR139, Probable G-protein-coupled receptor 139
    • 1.279. FOXP2
    • 1.303. NR4A2, NURR1, Nuclear Receptor Subfamily 4 Group A Member 2
    • 1.122. CSMD1, CUB, and Sushi Multiple Domains 1
  • Potassium channels influence dopamine
    • 1.85. KCNJ6, Potassium Inwardly Rectifying Channel Subfamily J Member 6
    • 1.67. DPP10, Dipeptidyl Peptidase-Like 10 (Chromosome 2q14.1)
    • 1.268. KCNC2, Potassium Voltage-Gated Channel Subfamily C Member 2
    • 1.100. DPP6, Dipeptidyl-Aminopeptidase-Like Protein 6
    • 1.64. KCNC1 (Chromosome 11p15.1)
    • 1.65. KCNIP4, Potassium Voltage-Gated Channel Interacting Protein 4 (Chromosome 4p15.3-p15.2)
    • 1.66. KCNIP1, Potassium Voltage-Gated Channel Interacting Protein 1
    • 1.256. ALG10, ALG10 Alpha-1,2-Glucosyltransferase
  • Other dopaminergic influences
    • 1.30. ADGRL3, LPHN3, Latrophilin-3 (Chromosome 4q13.1)
    • 1.296. SORCS3, Sortilin-Related VPS10 Domain-Containing Receptor 3
    • 1.76. DIRAS2; DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2 (Chromosome 9q22.2)
    • 1.90. TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1
    • 1.125. FERMT3, FERM Domain-Containing Kindlin 3
    • 1.82. GLI1; PPD1; GLI Family Zinc Finger 1
    • 1.307. DGKH; Diacylglycerol Kinase Eta
    • 1.101. EMP2, Epithelial Membrane Protein 2
    • 1.317. SYN3, Synapsin III
    • 1.318. SYN1, Synapsin 1
  • 1.282. PTPRF, Protein Tyrosine Phosphatase Receptor Type F
  • 1.199. CSMD1, CUB, and Sushi Multiple Domains 1
• Norepinephrine
  • Norepinephrine synthesis
    • 1.7. DBH, dopamine beta-hydroxylase (chromosome 9q34.2; Taql A)
  • Effects of norepinephrine
    • 1.46. ADRA1A, ALPHA-1A-ADRENERGIC RECEPTOR (Chromosome 8p21.2)
    • 1.17. ADRA2A, ALPHA-2A-ADRENERGIC RECEPTOR (Chromosome 10q25.2)
    • 1.69. ADRA2C, ALPHA-2C-ADRENERGIC RECEPTOR (Chromosome 4p16.3)
    • 1.44. ADRB2, BETA-2-ADRENERGIC RECEPTOR (Chromosome 5q32)
  • Norepinephrine breakdown
    • Norepinephrine reuptake
      • 1.18. NET, norepinephrine transporter gene (chromosome 16q12.2)
    • Development of the Norepinephrine System
      • 1.329. MECP2
• Serotonin
  • Serotonin synthesis
    • 1.16. Tryptophan hydroxylase gene (chromosome 11p15.1)
    • 1.77. TPH1, tryptophan hydroxylase-1 gene (chromosome 11p15.1)
    • 1.21. TPH2, tryptophan hydroxylase 2 gene (chromosome 12q21.1)
  • Effects of Serotonin
    • 1.13. HTR1B, Serotonin Receptor 1B (Chromosome 6q14.1)
    • 1.51. HTR1E, Serotonin Receptor 1E (Chromosome 6q14.3)
    • 1.14. HTR2A, serotonin receptor 2A (chromosome 13q14.2)
  • Serotonin breakdown
    • Serotonin reuptake
      • 1.15. SLC6A4, serotonin transporter gene, 5-HTT gene (chromosome 17q11.2)(x)
    • Serotonin Metabolism
      • 1.20. Tryptophan 2,3-dioxynase (Chromosome 4q32.1)
• Steroids
  • 1.19. Androgen receptor (chromosome Xq11-q12)
• GABA
  • 1.162. SLC6A12, GABA transporter
  • 1.319. SLC6A1, GABA transporter
  • 1.22. GABA receptor alpha-3 (chromosome Xq28)
  • 1.23. GABA receptor beta-3 (chromosome 15q11.2-q.12)
  • 1.35. CDH13, Cadherin 13 (Chromosome 16q23.3)
  • 1.116. KIF21B, Kinesin Family Member 21B
• Acetylcholine
  • Acetylcholine action
    • 1.32. CHRNA7, Alpha-7 neuronal nicotinic acetylcholine receptor
    • 1.50. CHRNA4, Alpha-4 neuronal nicotinic acetylcholine receptor (chromosome 20q13.33)
    • 1.212. LYPD1, LY6/PLAUR Domain-Containing 1
• Choline
  • Choline breakdown
    • 1.40. SLC5A7, CHT1, CHOLINE TRANSPORTER
    • 1.237. SLC44A1, Solute Carrier Family 44, Member 1
• Glutamate
  • 1.39. GRM1, Metabotropic Glutamate Receptor 1 (Chromosome 6p24-3)
  • 1.225. GRIK3, Glutamate Ionotropic Receptor Kainate Type Subunit 3
  • 1.312. GRIK1, Glutamate Ionotropic Receptor Kainate Type Subunit 1
  • 1.34. GRM5, Metabotropic glutamate receptor 5 (Chromosome 11q14..2 – 14.3) (33, p. 55)
  • 1.38. GRM7, Metabotropic glutamate receptor 7 (Chromosome 3p26.1)
  • 1.43. SLC9A9, Solute Carrier Family 9 Member A9 (Chromosome 3q24)
• Cannabinoids
  • 1.37. CNR1, Cannabinoid Receptor 1 (Chromosome 6q14-q15) (x)
  • 1.401. FAAH (x)
• Trace amines
  • 1.42. PNMT, Phenylethanolamine N-Methyltransferase (Chromosome 17q12)
• Glycine
  • 1.89. SLC6A9, Glycine Transporter
• Nitric oxide
  • 1.36. NOS1, Nitric Oxide Synthase 1 (Chromosome 12q24.22) (87)
• Neurotransmitter Storage and Release
  • 1.114. CPLX2, Complexin 2
  • 1.177. STXBP6, Syntaxin-Binding Protein 6
  • 1.242. MYO5B, Myosin VB
  • 1.263. TRAPPC11, Trafficking Protein Particle Complex Subunit 11
• Fatty acids
  • 1.48. FADS2, FATTY ACID DESATURASE 2 (Chromosome 11q12.2)
  • 1.366. GALC
  • 1.367. SMPD1
  • 1.368. CERS6
  • 1.369. CERS2
• Brain Development
  • 1.33. NDE1, Nuclear Distribution Gene E Homolog 1
  • 1.106. MAP1B, Microtubule-Associated Protein 1B
  • 1.107. MOBP, Myelin-Associated Oligodendrocyte Basic Protein
  • 1.56. ASTN2, ASTROTACTIN 2 (Chromosome 9q33.1)
  • 1.110. TCF4, Transcription Factor 4
  • 1.111. TLL2, Tolloid-Like 2
  • 1.117. TENM4, Teneurin Transmembrane Protein 4
  • 1.91. ANK3, ANKYRIN 3
  • 1.120. ANKS1B, Ankyrin Repeat and Sterile Alpha Motif Domain-Containing 1B
  • 1.233. EPHA7, EPH Receptor A7
  • 1.299. SEMA6D, Semaphorin 6D
  • 1.63. NAV2, NEURON NAVIGATOR 2 (Chromosome 11p15.1)
  • 1.119. CNNM2, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 2
  • 1.324. DLG4 / PSD-95
  • 1.325. FEZ1
• Growth Factors, Neurogenesis
  • 1.25. NTF3, neurotrophin 3 (chromosome 12p13.31)
  • 1.71. NTF4, NEUROTROPHIN 4 (Chromosome 19q13.33)
  • 1.26. BDNF, Brain-Derived Neurotrophic Factor (Chromosome 11p14.1) (X)
  • 1.27. BAIAP2, Brain-specific angiogenesis inhibitor 1-associated protein
  • 1.70. NGF, NERVE GROWTH FACTOR (Chromosome 1p13.2)
  • 1.72. GDNF, GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR (Chromosome 5p13.2)
  • 1.54. UNC5, C. elegans homolog, B; UNC5B (Chromosome 10q22.1)
  • 1.61. GPC6, GLYPICAN 6 (Chromosome 13q31.3-q32.1)
  • 1.232. CNTN5, Contactin 5
• Cell Development
  • 1.298. POC1B, POC1 Centriolar Protein B
  • 1.62. CTNNA2, CATENIN ALPHA-2 (Chromosome 2p12)
• Circadian Rhythm
  • 1.29. CLOCK, Clock Circadian Regulator (Chromosome 4q12) (x)
  • 1.261. PER1, Period Circadian Regulator 1 (Chromosome 2q37.3)
  • 1.47. PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2 (Chromosome 2q37.3)
  • 1.73. Vasoactive Intestinal Peptide Receptor 2; VIPR2 (Chromosome 7q36.3)
  • 1.79. KAT2B, LYSINE ACETYLTRANSFERASE 2B
  • 1.84. CADM1, CELL ADHESION MOLECULE 1 (TSLC1, IGSF4); CADM2, CELL ADHESION MOLECULE 2
  • CRY1
  • 1.375. BMAL1
  • 1.341. Neuropeptide Y (NPY)
  • 2.52. MTA3, METASTASIS-ASSOCIATED GENE 3 (Chromosome 2)
• Immune System
  • 1.57. CSMD2, CUB AND SUSHI MULTIPLE DOMAINS 2 (Chromosome 1p35.1)
  • 1.112. TRIM26, Tripartite Motif Containing 26
  • 1.210. MYO1G, Myosin IG
  • 1.230. TLR4, Toll-like receptor 4
• Stress Systems
  • HPA axis
    • 1.74. NR3C1, Nuclear Receptor Subfamily 3 Group C Member 1, Glucocorticoid Receptor (Chromosome: 5q31.3)
    • 1.75. FKBP5, FK506-BINDING PROTEIN 5 (Chromosome 6p21.31)
    • 1.60. CDH23, CADHERIN 23 (Chromosome 10q22.1)
    • 1.254. NAT2, N-acetyltransferase 2
  • Oxidative Stress
    • 1.297. DUSP6, Dual-Specificity Phosphatase 6
  • Other Consequences of Stress
    • 1.108. NCL, Nucleolin
• Broad-spectrum mechanisms
  • Transcription
    • 1.95. RERE
    • 1.45. HES1; HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1 (Chromosome 3q29)
    • 1.86. FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1
    • 1.143. ZNF763, Zinc Finger Protein 763
    • 1.134. ZNF615, Zinc Finger Protein 615
    • 1.139. POLR1H, RNA Polymerase I Subunit H
  • Receptor activity
    • 1.41. ARRB2, Arrestin Beta-2 Gene (Chromosome 17p13.2)
  • Neurotransmitter Storage
    • 1.49. SYP, SYNAPTOPHYSIN (Chromosome Xp11.23)
  • Purine metabolism
    • 1.115. NT5C2, 5’-Nucleotidase, Cytosolic II
  • Adhesion
    • 1.288. PCDH7, Protocadherin 7
    • 1.53. SPATA13, SPERMATOGENESIS-ASSOCIATED PROTEIN 13 (Chromosome 13q12.12)
    • 1.58. ITGAE, Integrin Subunit Alpha E (Chromosome 17p3.2)
    • 1.59. ITGA11, Integrin Subunit Alpha 11 (Chromosome 15q23)
• Brain damage
  • 1.287. SPAG16, Sperm-Associated Antigen 16
• Astrocytes
• 2.83. SNORC, Secondary Ossification Center-Associated Regulator of Chondrocyte Maturation
• 1.152. ALS2CR8, CARF
• 1.365. GFOD1, glucose-fructose oxidoreductase domain 1

ADHD candidate genes with a plausible mechanism of action related to ADHD¶

Dopamine¶

Dopamine synthesis¶

1.8. DDC, AADC, Aromatic L-Amino Acid Decarboxylase (Chromosome 9q34.2)¶

Other names: DOPA-dercaboxylase

OMIM: DOPA decarboxylase gene, DDC

DDC is a candidate for ADHD.¹
A DDC deficiency increases the likelihood of ADHD symptoms.²

In a 2006 study, the DDC gene was identified as a candidate gene for ADHD with a p-value of 0.039.³

A study found reduced striatal and prefrontal dopamine decarboxylase activity in children with hyperactivity (but not in adults).⁴

Hayley note that while loss-of-function (LOF) mutations in the DDC gene have been associated with severe neurodevelopmental delays, hypotonia, oculogyric crises, and complex movement disorders with autonomic features, no typical ADHD symptoms have been described.⁵ Since the subjects in the first cited study were mostly children under one year of age, this comes as no surprise to us.⁶ Although the second cited study also examined older participants, no ADHD symptoms other than irritability were assessed—presumably because the other DDC deficiency symptoms are significantly more severe and diagnostically meaningful. Irritability was confirmed.⁷ Two authors of the latter study contributed to the review cited above—which identified an increased risk of ADHD associated with DDC deficiency and was published three years earlier.² Against this background, we continue to consider DDC-LOF gene variants as candidate genes for ADHD.

DDC has a wide range of substrates and is involved not only in the synthesis of dopamine, but also in that of histamine, serotonin, and norepinephrine.

1.9. TH, Tyrosine Hydroxylase (Chromosome 11p15.5)¶

Other names: Tyrosine 3-monooxygenase; DYT5b; Tyrosine 3-hydroxylase; EC 1.14.16.2; TYH; Dystonia 14; EC 1.14.16; DYT14

The TH protein catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, norepinephrine, and epinephrine. TH uses tetrahydrobiopterin and molecular oxygen to convert tyrosine into L-Dopa. In addition to tyrosine, TH can also catalyze the hydroxylation of phenylalanine and tryptophan with lower specificity. TH positively regulates the regression of retinal hyaloid vessels during postnatal development. Isoform 5 and isoform 6 exhibit no catalytic activity.⁸
TH is affiliated with

• Segawa syndrome, autosomal recessive
• Dystonia

Related signal paths:

• dopaminergic neurogenesis
• Metabolism of amino acid-based hormones
• Enzyme binding
• Oxygen binding

Paralog: PAH

Tyrosine hydroxylase is a candidate gene for ADHD.¹

1.121. AS3MT, Arsenite Methyltransferase¶

Other names: CYT19, S-Adenosyl-L-Methionine:Arsenic(III) Methyltransferase, Arsenic (+3 Oxidation State) Methyltransferase, Methylarsonite Methyltransferase, S-Adenosylmethionine:Arsenic (III) Methyltransferase, Methyltransferase Cyt19, EC 2.1.1.137

The protein AS3MT plays a role in arsenic metabolism. AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to trivalent arsenic, resulting in methylated and dimethylated arsenic compounds. AS3MT methylates arsenite to methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate reductase to methylarsonite, Me-As(OH)2. Methylarsonite is also a substrate and is converted into the significantly less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH.

AS3MT is associated with

• Borst-Jadassohn Intraepidermal Carcinoma
• ADHD
• Epilepsy⁹

AS3MT rs7085104 is associated with a change in the striatal dopamine synthesis capacity **** .⁹

A study identified AS3MT as one of the 51 most likely genetic candidates for ADHD.¹⁰

FAH, fumarylacetoacetate hydrolase¶

Other names: Fumarylacetoacetase; Beta-diketonase; EC 3.7.1.2; FAA; Fumarylacetoacetate Hydrolase (Fumarylacetoacetase); Epididymal Secretory Sperm-Binding Protein; FUMARYLACETOACETATE HYDROLASE

FAH encodes a protein that mediates fumarylacetoacetase activity. It appears to be involved in L-phenylalanine catabolism, homogentisate catabolism, and tyrosine catabolism. It appears to act upstream of or within the arginine degradation process. FAH is located in the extracellular exosome.¹¹
FAH is affiliated with

• Tyrosinemia Type I (HT1, TT-1)

Paralog: FAHD2B.

Tyrosinemia (here: Hereditary Tyrosinemia Type 1, HT-1, or TT-1), a rare disorder of tyrosine metabolism that leads to elevated tyrosine levels, is associated with increased inattention.¹²¹³

GCH1¶

GCH1 (GTP cyclohydrolase 1) encodes the rate-limiting enzyme in the production of tetrahydrobiopterin, which in turn is an essential cofactor for the synthesis of dopamine, serotonin, and nitric oxide.
The functional single-nucleotide polymorphism (SNP) in the GCH1 gene, rs841 (C+243T), correlates with reduced attentional performance (particularly sustained attention and vigilance) on the Continuous Performance Test—Identical Pairs Version (CPT-IP) in healthy individuals.¹⁴¹⁵

Dopamine Storage and Release¶

1.28. SNAP25, Synaptosome-Associated Protein 25 (Chromosome 20p12.3; T1065G)¶

Other names: SNAP-25; DJ1068F16.2; BA416N4.2; RIC-4; RIC4; SEC9; SNAP; Resistance to Inhibitors of Cholinesterase 4 Homolog; Synaptosomal-Associated Protein, 25 kDa; Synaptosomal-Associated Protein 25; SUP; Synaptosomal-Associated 25 kDa Protein; Synaptosome-Associated Protein 25 kDa; Super Protein; CMS1

The SNARE protein SNAP-25— —together with syntaxin-1 and synaptobrevin—mediates the release of neurotransmitters from synaptic vesicles in neurons.
SNAREs ( , soluble N-ethylmaleimide-sensitive factor attachment protein receptors) mediate the docking and fusion of synaptic vesicle membranes located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is provided by v-SNARE and the other three by t-SNARE. For the t-SNAREs on the plasma membrane, the protein syntaxin contributes one helix, and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. SNAP25 regulates plasma membrane recycling through its interaction with CENPF. SNAP25 modulates the gating properties of the voltage-gated potassium channel KCNB1 with delayed rectification in pancreatic beta cells.¹⁶
SNAP25 is associated with

• Myasthenic syndrome, congenital, 18
• Developmental and Epileptic Encephalopathy

Related signal paths:

• Neurotransmitter release cycle
• wtCFTR and delta508-CFTR traffic / Generic scheme (standard and CF)
• Calcium-dependent protein binding
• SNAP receptor activity

Paralog: SNAP23

OMIM: 25-kD synaptosomal-associated protein gene / SYNAPTOSOMAL-ASSOCIATED PROTEIN, 25-KD; SNAP25

SNAP25 is a candidate gene for ADHD.¹¹⁷ SNAP25 was identified as a candidate gene for ADHD in a 2006 study with p = 0.035.³

1.275. SYT1, Synaptotagmin 1¶

Other names: P65; Synaptotagmin I; SVP65; SYT; Synaptotagmin-1; SytI; BAGOS

Synaptotagmins are integral membrane proteins of synaptic vesicles that are thought to function as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. The binding of calcium to synaptotagmin-1 is involved in triggering neurotransmitter release at the synapse.
SYT1 is a calcium sensor involved in triggering neurotransmitter release at the synapse. SYT1 may regulate membrane interactions during the transport of synaptic vesicles in the active zone of the synapse. SYT1 binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. There appears to be a Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C. SYT1 plays a role in the dendrite formation of melanocytes. SYT1 can bind to at least three other proteins in a Ca(2+)-independent manner:¹⁸

• Neurexin
• Syntaxin
• AP2

While Syt7 (synaptotagmin 7), a high-affinity Ca2+ sensor, underlies phasic somatodendritic dopamine release and its Ca2+ sensitivity in the substantia nigra pars compacta, , SYT1 acts as a Ca²⁺ sensor for axonal dopamine release and plays a role in tonic, but not phasic, somatodendritic dopamine release. However, SYT1 can facilitate phasic dopamine release when SYT7 is inactivated. SYT1 and SYT7 function as Ca²⁺ sensors that support different aspects of somatodendritic dopamine release.¹⁹

SYT1 is associated with:

• Baker-Gordon syndrome
• Syndromic Intellectual Disability

Related signal paths:

• Neurotransmitter release cycle
• Calcium ion binding
• Transporter activity

Paralog: SYT2

SYT1 was identified as a candidate gene for ADHD in a 2008 study. It is believed to correlate with general ADHD symptoms.²⁰

2.99. DNM1, Dynamin 1¶

Other names: DNM, EC 3.6.5.5, Dynamin-1, EIEE31, DEE31

The DNM1 protein is a member of the dynamin subfamily of GTP-binding proteins. DNM1 possesses unique mechanochemical properties that are utilized for membrane tubulation and cleavage, and it is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble, leading to the stimulation of GTPase activity.²¹
Connected signal paths:

• Integrin pathway
• Development of the nervous system.

Mutations in DNM1 are associated with

• Autism²²
• Epileptic encephalopathy²³
  • infantile spasms with onset between 2 and 13 months
  • subsequent development of Lennox-Gastaut syndrome
  • severe to profound intellectual disability
  • severe hypotension
  • Missing language.

Most pathogenic variants are missense variants that have been shown to impair the endocytosis of synaptic vesicles In a dominant-negative manner.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

Dopamine Effects¶

1.1. DRD1, dopamine receptor D1 (chromosome 5q35.2)¶

OMIM: Dopamine D1 receptor gene, DRD1

DRD1 is a candidate gene for ADHD.¹

The DRD1 receptor is closely related to the DRD5 receptor, but is found in different brain regions, namely the striatum, nucleus accumbens, tuberculum olfactorium, and the frontal cortex—that is, in brain regions where DRD1 receptors are barely found.²⁴

1.2. DRD2, dopamine receptor D2 (chromosome 11q23.1; TAQ1A, rs1800497)¶

OMIM: Dopamine D2 receptor gene, DRD2
DRD2 is a candidate gene for ADHD.¹

In several studies, the A allele has been associated with a lower receptor density in the striatum. This means that dopamine can be taken up to a lesser extent, which has the same effect as a reduced dopamine level.²⁵
The DRD2-A1 allele is said to be associated with impulsivity, compulsivity, and addiction.²⁶

A study found a significantly increased overlap in the risk of ADHD and ASD correlated with the DRD2-12 (rs7131465) gene polymorphism.²⁷

The DRD2 gene variants rs6277 and rs6275 were significantly correlated with ADHD in boys and girls, respectively. In addition, a significant association was found between DRD2 rs6275 and SCLA6A3 (DAT1) rs1012586. The interaction between the GRIN2B and DRD2 genes may contribute to the susceptibility of Chinese children to ADHD.²⁸

1.3. DRD3, dopamine receptor D3 (chromosome 3q13.31)¶

OMIM: Dopamine D3 receptor gene, DRD3
DRD3 is a candidate gene for ADHD.¹

In mice, the D3 receptor was found to influence increased motor activity (hyperactivity) and rearing behavior. Binding to the D3 receptor prevents addictive behavior (craving).

The DRD3 rs6280 T allele was associated with a reduced risk of ADHD, and the TT genotype was also associated with a reduced risk.{Ansari MA, Naqvi HA, Khidri FF, Rajput AH, Mahmood A, Waryah AM (2024): Gene-gene and gene-environmental interactions of dopaminergic system genes in Pakistani children with attention deficit hyperactivity disorder. Saudi J Biol Sci. Aug 2024;31(8):104045. doi: 10.1016/j.sjbs.2024.104045. PMID: 39050560; PMCID: PMC11268355.}}

1.4. DRD4, dopamine receptor D4 (chromosome 11p15.5, exon III, VTNR) (x)¶

OMIM: Dopamine D4 receptor gene, DRD4

DRD4 is a candidate gene for ADHD.^2917130
In a 2006 study, DRD4 was identified as a candidate gene for ADHD with a p-value of 0.055.³
The DRD4-7R variant increases the risk of ADHD by 50% (odds ratio 1.5).³¹
The 7-repeat allele encodes the dopamine D4 receptor in such a way that it requires three times the amount of dopamine to respond. ³²³³ This results in what appears to be a reduced dopamine level in the striatum, which correlates with motivational problems and impulsivity.³⁴
In other words, DRD4-7R results in reduced postsynaptic inhibition.³⁵³⁶
A recent report suggests that DRD4-7R is not simply less sensitive to dopamine, but rather interacts with other dopamine receptors. Furthermore, like all D2-type receptors (D2, D3, and D4), DRD4 is also said to respond to norepinephrine as an agonist.³⁷

DRD4-7R ultimately increases the reactivity of the ventral striatum.
DRD4-7R therefore does not in and of itself cause lower dopamine levels in the striatum, but rather reduces inhibition of the striatum by initially responding to higher dopamine levels with inhibition.
Surprisingly, however, DRD4-7R also has an inhibitory effect on the methamphetamine-induced increase in dopamine and glutamate in the striatum. A methamphetamine-induced increase in dopamine and glutamate was reduced in mice with the DRD4-7R gene.³⁸ In contrast, no reduction in the increase in dopamine or glutamate was observed with cocaine in the DRD4-7R variant. The increase in dopamine in response to cocaine was significant across all DRD4 variants, while the increase in glutamate was relatively small.
Striatal glutamate stimulates an increase in dopamine levels in the striatum.³⁸
Adenosine modulates striatal DA release by stimulating glutamate release via adenosine receptors in the striatum, which increases dopamine levels.³⁹
DRD4-7R results in reduced function and connectivity in brain regions involved in inhibitory control during the performance of impulse control tasks, particularly the right inferior frontal gyrus.³⁸⁴⁰⁴¹
Diminished corticostriatal neurotransmission impairs GABAergic activity in the striatum during “Go” and “NoGo” tasks and reduces the ability to increase reactivity to reward-related stimuli and suppress it in response to non-reward-related or aversive stimuli.⁴²
This increases “interest” in irrelevant stimuli and reduces inhibition of irrelevant responses, as evidenced by distractibility and impulsivity in behavior and decision-making in ADHD.³⁸ This contradicts the claims that the DRD4-7R allele is associated with the ADHD-I subtype.

We assume that DRD4-7R is associated with increased impulsivity, which is more typical of the ADHD-HI subtype.
DRD4-7R is associated with novelty seeking.⁴⁹ Novelty seeking correlates with high impulsivity.
A cohort study found that the DRD4-7R variant was generally associated with high levels of hyperactivity/impulsivity.⁵⁰
DRD4-7R results in reduced formation of gyri and sulci (gyrification) in the PFC of people with ADHD.⁵¹

DRD4-7R is only about 40,000 to 50,000 years old and has since spread much more rapidly than would be expected from random genetic transmission. This suggests that DRD4-7R is an extremely successful gene.³⁶⁵²

DRD4-4R and DRD4-7R appear to have a strong and distinct influence on the function of the D2-short receptor variant.⁵³

The DRD4 variants Dup 120bp and VNTR 48bp are involved in the etiology of ADHD in adults. A gene-environment analysis revealed an independent effect of stress experiences on the severity of ADHD persisting into adulthood and a gene-environment interaction regarding inattention, with non-carriers of the Dup 120bp (L) - VNTR 48bp (7R) haplotype were more sensitive to environmental stressors than carriers.⁵⁴
Genetic epistasis between DRD4 and MAOA variants has been described, with the MAOA variants influencing the effect of the DRD4 variants.⁵⁵

A review article on the epigenetic causes of ADHD highlights the relevance of DRD4.⁵⁶

1.5. DRD5, dopamine receptor D5 (chromosome 4p16.1-p15.3; CARepeat, 148 bp)¶

OMIM: Dopamine receptor D5 gene, DRD5

DRD5 is a candidate gene for ADHD.¹⁷¹

The DRD5 receptor is closely related to the DRD1 receptor, but is found in other (primarily limbic) brain regions, namely the hippocampus, mamillary nuclei, anterior pretectal nuclei, and all brain regions in which DRD1 receptors are barely found.²⁴
The DRD5 receptor is widely distributed in the brain and has a significantly higher affinity for dopamine than the D1 receptor. The DRD5-148-bp allele, located 18.5 kb at the 5′ end of the flanking region, is associated with ADHD.⁵⁷
DRD5 appears to modulate the hypothalamus and parts of the motor control system.⁵⁸

1.234. ADORA2A, ADENOSINE A2A RECEPTOR¶

Other names: ADORA2; RDC8; Adenosine Receptor A2a; Adenosine Receptor Subtype A2a; A2aR

OMIM: ADENOSINE A2A RECEPTOR; ADORA2A

The ADORA2 protein is the adenosine A2a receptor. ADORA2 is a member of the superfamily of guanine nucleotide-binding protein (G-protein)-coupled receptors (GPCRs), which are divided into classes and subtypes. These receptors are seven-pass transmembrane proteins that respond to extracellular stimuli and activate intracellular signal transduction pathways. ADORA2 uses adenosine as its preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) families of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions, such as heart rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. A2A receptors are highly expressed in the spleen, thymus, leukocytes, platelets, and the olfactory bulb.⁵⁹
ADORA2 is affiliated with

• Acute encephalopathy with biphasic seizures and delayed diffusion reduction
• Basal ganglia disorder
• Inflammatory diseases
• neurodegenerative disorders

Paralog: ADORA2B

A possible significant association between the A2AAR gene polymorphism rs35320474 and ADHD has been reported.⁶⁰
Another study reports a correlation between the rs5751876 TC genotype in children with ADHD and the rs2298383 CC genotype in children with ADHD-HI; however, this correlation was no longer significant after Bonferroni correction.⁶¹

Adenosine is very closely linked to the effects of dopamine. Adenosine A2A receptors and dopamine receptors form receptor heterodimers. Adenosine inhibits dopamine via the A2A receptor. For more on this, see Adenosine.

1.109. PPP2R2B, Protein Phosphatase 2 Regulatory Subunit B beta¶

Other names: PR55-BETA, PR52B, Serine/Threonine Protein Phosphatase 2A 55 kDa Regulatory Subunit B Beta Isoform, PP2A Subunit B Isoform Beta, B55beta, SCA12, Protein Phosphatase 2 (formerly 2A), Regulatory Subunit B (PR 52), Beta Isoform, Protein Phosphatase 2, Regulatory Subunit B, Beta, PP2A Subunit B Isoform PR55-Beta, PP2A Subunit B Isoform B55-Beta

The protein PPP2R2B belongs to the family of protein Ser/Thr phosphatases. These are a group of enzymes that catalyze the removal of phosphate groups from serine and/or threonine residues through the hydrolysis of phosphoric acid monoesters. They counteract the effects of kinases and phosphorylases and are involved in signal transduction and the inhibition of cell growth and division.
PPP2R2B modulates the substrate selectivity and catalytic activity of the enzyme, as well as its localization within a specific subcellular compartment. Isoform 2 is required for promoting proapoptotic activity and regulates neuronal survival by balancing mitochondrial fission and fusion.⁶²

PPP2R2B is associated with

• autosomal dominant spinocerebellar ataxia 12 (SCA12; degeneration of the cerebellum and, in some cases, the brainstem and spinal cord; poor coordination of speech and body movements)
• autosomal dominant cerebellar ataxia

PPP2R2B and Dopamine:
The signaling function of dopamine receptors is not limited to the regulation of cAMP production. Some receptors can couple to GαQ G proteins to regulate intracellular inositol and calcium signaling. Furthermore, the activation of Gβγ G-protein subunits by DRD2 leads to neuronal hyperpolarization by regulating the activity of L- and N-type calcium channels (LTCC and NTCC) and G-protein-regulated inward-directed potassium channels (e.g., GIRK2/KCNJ6).⁶³ Furthermore, DRD2 modulates neuronal function by acting on G-protein-independent mechanisms. Upon activation, dopamine receptors are phosphorylated by G-protein-coupled receptor kinases (e.g., GRK2, GRK6). This leads to the recruitment of beta-arrestins (ARBB1 and ARBB2), which inactivate G-protein coupling, stimulate receptor internalization, and mediate other cellular signaling functions. In the case of DRD2, the recruitment of ARBB2 leads to the formation of a protein complex that mediates the inactivation of protein kinases from the Akt family (AKT1, AKT2, AKT3) by protein phosphatase 2 holoenzymes (i.e., PPP2R2B, PPP2CA, PPP2CB). The inactivation of AKT kinases downstream of DRD2 triggers the inhibition of glycogen kinase-3 family proteins (GSK3A, GSK3B), thereby increasing their activity.⁶⁴

An SNP associated with PPP2R2B expression (rs959627) appears to predict prefrontal activity during the N-back working memory task.
The rs959627T allele was correlated with:⁶⁵

• reduced PPP2R2B expression in the PFC
• increased activity in the right inferior frontal gyrus (IFG) during the N-back task
• poorer performance on the N-back task
• reduced efficiency of the right IFG during working memory processing

A study identified PPP2R2B as one of the 51 most likely genetic candidates for ADHD.¹⁰ Another study found that the PPP2R2B rs9325032 variant was the gene most strongly associated with ADHD.⁶⁶

SORCS2¶

The SORCS2 gene is a candidate gene for ADHD.⁶⁷

See also our description of SORCS2-/- mice and the discussion therein of the dopaminergic effects of SORCS2.

Dopamine degradation¶

Dopamine reuptake¶

1.6. SLC6A3, DAT1, dopamine transporter gene (chromosome 5p15.3; 10-R allele, VNTR)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3

OMIM: SLC6A3 (DAT1) SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3;

The dopamine transporter (DAT), which plays the primary role in dopamine reuptake, is found primarily in the striatum⁶⁸ and only in small amounts in the PFC.

To illustrate the diversity of gene variants, we cite the 73 DAT1 gene variants identified by 2014 and compiled by Mergy et al., none of which were associated with any known disease: K3N; M11I; M11V; S12P; V14M; A16T; P17L; E20(stop); E20V; I32M; V24A; G39R; L42F; P50L; S53R; V73; L104I; G121S; V131I; L138P; L138R; A161T; A163V; A192T; S198T; S202L; S202W; G209R; V221M; R237W; V245A; I268V; T271N; V275L; L281P; G289R; G293S; V300I; E307K; A308V; A314V; D345G; A346T; A346V; F362L; L368Q; Q373R; G380R; P395L; G433R; D436N; R445G; A455V; V464I; V471I; I490V; V501A; Q509H; R515W; S517T; G538A; V538I; R544S; P545T; H547Q; A559T; A576E; K579R; R588Q; G607W; R610H; T613M; K619N.⁶⁹

The DAT1 gene, which encodes DAT, is frequently cited as a candidate for ADHD.^{2917 1 30 3} in particular the DAT1 10/10 variant.⁷⁰
A specific DAT1 variant is said to be primarily associated with the ADHD-HI subtype.⁴³ DAT binding is linked to motor hyperactivity, but not to inattention.²⁹ In the ADHD-HI (hyperactive) subtype, the striatum is primarily affected. The caudate nucleus is noticeably reduced in size.⁷¹
A specific DAT1 gene variant results in an excessive number of dopamine transporters. An excessive number of dopamine transporters causes the dopamine released presynaptically (by the sending neuron) to be reabsorbed by the excess DATs—like a vacuum cleaner—back into the presynapse (the sending neuron) before it can be taken up postsynaptically (by the receiving neuron). Consequently, the correctly released amount of dopamine does not reach the postsynaptic dopamine receptors, which is why they do not receive the necessary amount of decision-making information (which would only be triggered once a sufficient number of receptors had received dopamine).⁴⁴⁷²
The relevant polymorphisms of the DAT gene occur significantly more frequently in families of people with ADHD (n = 329). A combination of three specific polymorphisms is associated with a 2.5-fold increase in the prevalence of ADHD.⁷³
Certain DAT1 variants are associated with a predisposition to lower birth weight and a susceptibility to ADHD.⁷⁴
Unlike the DAT Ala559 variant, DAT Val559 is thought to be associated with increased dopamine transport capacity, which could be relevant in ADHD, autism, and bipolar disorder.⁷⁵
The DAT variant Ala559Val (hDAT A559V) is thought to cause increased dopamine efflux, similar to that triggered by amphetamine. Tonic activation of DRD2 supports the hDAT A559V-mediated increased dopamine efflux. hDAT A559V possesses a pertussis toxin-sensitive, CaMKII-dependent phosphorylation mechanism that supports DRD2-mediated dopamine efflux.⁷⁶
hDAT VAL559 also exhibits increased dopamine efflux and is associated with ADHD, ASD, and BPD. KOR antagonists reduced the increased dopamine release observed at VAL559 in vivo. Similarly, the enhanced DAT-Thr53 phosphorylation and increased DAT trafficking observed in hDAT VAL559 were normalized. Conversely, KOR agonists increased DAT-Thr53 phosphorylation and DAT trafficking in the wild-type.⁷⁷

The DAT1 gene variant 12P572A is associated with increased DAT efflux and reduced dependence on ion or dopamine concentrations.⁷⁸
The SLC6A3 gene variant rs2652511 was significantly associated with ADHD in boys and girls, respectively. In addition, a significant association was found between DRD2 rs6275 and SCLA6A3 (DAT1) rs1012586.²⁸
The DAT1 rs27048 (C)rs429699 (T) haplotype was associated with altered functional connectivity of the left dorsal caudate nucleus during visual memory tasks in adolescents with ADHD in a study.⁷⁹

Rare coding DAT polymorphisms were found in people with ADHD and bipolar disorder.

• Val24Met⁸⁰
• Val55⁸¹
  • Val55A shows
  • increased dopamine Km
  • reduced affinity for cocaine
• Leu167Phe⁸⁰
• Arg237⁸¹
• Val382⁸¹
  • Ala substitutions in extracellular loop 4, which stabilize the extracellular gate
  • reduced dopamine affinity
  • increased affinity for cocaine
  • altered PKC-dependent regulation
• DAT-Asp421Asn⁸²
  • showed virtually no dopamine uptake
  • Computer simulations and in vivo experiments suggest that impaired sodium binding is the cause of the dysfunction
  • constitutive, abnormal dopamine efflux
  • a major cation leak that could further disrupt dopaminergic neurotransmission
• Ala559⁸¹
  • Val substitutions at the extracellular end of TM12 have been identified in people with ADHD, bipolar disorder, and autism⁸³
  • A559V⁸⁴
    • a very rare genetic variant
    • a threefold increase in dopamine efflux when cell membranes are depolarized
      • at the same level as that triggered by AMP in standard DAT
    • Both MPH and AMP blocked Ala559Val-mediated dopamine efflux
      • In wild-type hDAT, MPH and AMP increase it
    • increased sensitivity to intracellular Na+, but not to intracellular dopamine
    • possibly increased basal hDAT A559V phosphorylation, which is attenuated by AMP
    • normal DAT protein and cell surface expression
    • Normal dopamine (re)uptake⁸⁵ at both low and high dopamine levels
    • Normal effects of AMP, MPH, and cocaine on dopamine reuptake inhibition
    • an older woman who was a carrier of the A559V variant showed
      • high levels of hyperactivity/restlessness
      • high impulsivity/emotional vulnerability
      • High scores on the DSM-IV hyperactivity-impulsivity scale (over 90)
    • Increased efflux is CaMK-dependent and is mediated by DRD2⁸³
      • suggests the involvement of endogenous signaling and phosphorylation mechanisms
    • Increased PKCβ activity⁸³
    • releases DA through the fusion of synaptic vesicles, triggered by afferent electrical stimulation, followed by efficient DAT-mediated DA reuptake, which inactivates DA signaling
• Val559⁸⁶⁷⁷
  • DAT protein expression on the total and cellular surfaces comparable to that of Ala559
  • DA transport kinetics comparable to those of Ala559
  • abnormal DA efflux
    • an abnormal, DAT-mediated, outward-directed “leak” of cytoplasmic DA when cells are preloaded with DA
    • voltage-dependent; DA efflux is more pronounced at depolarized membrane potentials
    • DA efflux parallel to vesicular DA release
      • results in the loss of the close coupling between DA release and afferent input
      • Even a single transporter encoding Val559 can increase DA efflux and the risk of ADHD
    • AMP increases intracellular Na+, which promotes DA efflux⁸⁷
    • AMP did not induce DA efflux in cells transfected with DAT Val559; rather, it acted solely as a DAT antagonist and blocked DA efflux
    • Treatment with psychostimulants
      • Reduces DA clearance by blocking DAT
      • simultaneously prevents DA efflux
      • restores a more normal relationship between DA neuron activity and extracellular DA levels overall
• Glu602⁸¹
• Arg615Cys⁸⁸⁸¹
  • at the C-terminal CaMK binding site
  • Cys substitution of this residue causes numerous regulatory changes associated with chronically downregulated DAT, including:
    • increased transporter phosphorylation
    • reduced Flot1 binding
    • reduced distribution of membrane rafts
    • PKC- or AMP-induced endocytosis is reduced
  • a 50% reduction in DAT levels on the cell surface
  • correspondingly reduced DA transport rate
  • Shift in surface distribution from regulated to constitutive recycling
  • increased association with calcium/calmodulin-dependent protein kinase II (CaMKII)
  • Impaired localization in GM1-ganglioside-enriched membrane microdomains.

DAT dysfunction is also associated with Parkinson’s disease. All people with early-onset (childhood or adolescent) parkinsonism exhibited severely reduced DAT function (homozygous for a dysfunctional variant or two heterozygous dysfunctional DAT variants). The more severe the DAT dysfunction, the earlier Parkinsonism developed. Most people with ADHD carried previously unknown de novo variants. The dysfunctions were diverse: reduced dopamine binding affinity, reduced cell surface transporter activity, loss of posttranslational glycosylation of the dopamine transporter, and failure of amphetamine-mediated dopamine efflux.⁸⁹ The following DTDS-DAT variants were identified:

• Homozygous
  • C.941C>T –> Ala314Val (3 out of 8 people with ADHD)
  • C.1269 + 1G>A –> unknown (2 out of 8 people with ADHD); another study also reported this variant⁹⁰
  • C.1408_1409delinsAG –> Tyr470Ser (1 of 8 people with ADHD)
• Combination of two dysfunctional DAT variants:
  • 1 in 8 people with ADHD:
    • C.287-5_287-2delinsAAC –> unknown
    • C.1156G>A –> Gly386Arg
  • 1 in 8 people with ADHD:
    • C.254G>T –> Arg85Leu
    • C.1333C>T –> Arg445Cys
      • AMP demonstrated a certain transport capacity with this variant
      • No dopamine efflux
        • Neither through AMP
        • Or directly into the cytoplasm via 2 mM dopamine

Other rare DAT gene variants that are not associated with ADHD:

• I312F⁸⁵
  • rare DAT1 gene variant
  • impaired dopamine uptake with changes in ligand binding, ion coordination, and significant conformational disturbances
  • resulted in increased uncoupled anion conductivity
  • DAT-Ile312Phe
    • showed a significantly reduced capacity to take up dopamine
    • maintained membrane alignment
    • Both indicate impaired catalytic activity
    • Computer simulations and uptake experiments suggest that the impaired function of the DAT-Asp421Asn mutant is due to impaired sodium binding, which is consistent with the fact that Asp421 coordinates sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, abnormal efflux of dopamine, and electrophysiological analyses revealed a large cation leak that could further disrupt dopaminergic neurotransmission
• T356M
  • rare DAT1 gene variant
  • cocaine-sensitive release of cations, enhanced by Zn2+
  • reduced dopamine reuptake⁸⁵
    • DAT expression in the striatum remains unchanged
    • Vmax of the resumption is reduced
    • Reduced uptake has consequences that result in
      • D2R desensitization
      • reduced dopamine synthesis due to increased synaptic dopamine levels
      • reduced total dopamine content in the tissue
      • reduced phosphorylation of tyrosine hydroxylase at Ser31
      • synaptic hyperdopaminergia
      • increased striatal dopamine metabolism
  • sustained DA efflux⁹¹
  • reduced DAT affinity for cocaine and MPH (suggesting that T356 plays an important role in inhibitor binding)⁸⁵
    • DA peak release in response to cocaine is similar to that in the wild-type
    • The decay time of the amperometric current is significantly longer in DAT T356M+/+ mice than in wild-type mice, corresponding to reduced reuptake
  • reduced body weight
  • plays a role in ASD
  • Only T356M+/+ mice, not T356M+/- mice, exhibit behavioral abnormalities compared to wild-type mice
    • persistent spontaneous hyperactivity
      • reduced by DAT antagonists
        • ACT-01: within 20 minutes
        • GBR12909: within 10 minutes
    • repetitive behaviors
    • social deficits
      • Loss of interest in meeting new people
      • Loss of social dominance
    • Loss of motivated behavior or changes in behavioral choices (reduced marbles-burying behavior)
  • unchanged:
    • Strength
    • Coordination
    • motor learning
    • Anxiety
    • Stress response
• D421N⁸⁵
  • rare DAT1 gene variant
  • impaired dopamine uptake with changes in ligand binding, ion coordination, and significant conformational disturbances
  • cocaine-sensitive release of cations, not enhanced by Zn2+
• E602G⁸⁵
  • rare DAT1 gene variant
  • Replication unchanged compared to the wild type
• R615C⁸⁵
  • rare DAT1 gene variant
  • Replication unchanged compared to the wild type
  • impaired regulation⁸⁸
    • recycling as a fundamental part of the process
    • insensitive to the endocytic effects of AMPH and PKC (protein kinase C) activation
    • altered CaMKII (calcium/calmodulin-dependent protein kinase II) and flotillin-1 interactions
    • The C-terminus of DAT 615C may act dominantly to prevent AMPH regulation of wild-type DAT
• DAT1 gene variant Asn336 (ΔN336)⁹²
  • hDAT mutation
  • associated with ASD in humans
  • reduced dopamine uptake (nonexistent)
  • Dopamine efflux reduced to about one-third
  • in Drosophila:
    • Impaired social behavior during the escape
    • Hyperactivity
    • prolonged freezing and a reduced tendency to flee in response to predatory cues
    • increased anxiety
• T62D-hDAT⁹³⁹⁴
  • DAT expression is reduced
  • drastically reduced dopamine uptake (by 50%)
  • higher basal dopamine efflux
  • Zn(2+) at micromolar concentrations significantly enhanced dopamine uptake in T62D-hDAT, enabling the measurement of amphetamine-stimulated dopamine efflux.

The DAT1 rs6350 SNV AA genotype was associated with a significantly increased risk of ADHD, while the DAT1 rs6350 SNV AG genotype reduced the risk of ADHD.⁹⁵

1.18. SLC6A2, NET, norepinephrine transporter gene (chromosome 16q12.2)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NORADRENALINE), MEMBER 2

OMIM: Norepinephrine transporter gene, SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NOREPINEPHRINE), MEMBER 2; SLC6A2, NET

SLC6A2 is a candidate gene for ADHD.¹⁹⁶

The NET gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.012.³

Children with ADHD who have the SLC6A2 rs36011 haplotype (T) / rs1566652 (G) exhibited abnormalities in the intrinsic brain activity of the sensorimotor and dorsal attention networks, which correlated with impairments in visual memory and visual attention.⁹⁷

NET1-rs3785143 is thought to be associated with increased emotional lability in ADHD.⁹⁸

1.97. CACNA1C, Calcium Voltage-Gated Channel Subunit Alpha1 C¶

Other names: CACH2, CACN2, CACNL1A1, CCHL1A1, LQT8, TS, Voltage-Dependent Calcium Channel, L Type, Alpha 1C Subunit

The pore-forming alpha-1C subunit of the voltage-gated calcium channel that generates L-type calcium currents. It mediates the influx of calcium ions into the cytoplasm, thereby triggering the release of calcium from the sarcoplasm. Important for the excitation-contraction coupling in the heart. Essential for normal heart development and normal regulation of heart rhythm. Essential for the normal contraction of smooth muscle cells in blood vessels and the intestines. Essential for normal blood pressure regulation through its role in the contraction of arterial smooth muscle cells.⁹⁹
Acts as a receptor for influenza viruses. CACNA1C may play a role in facilitating viral entry when it is sialylated and expressed in lung tissue.
CACNA1C is associated with the following clinical diagnoses:¹⁰⁰

• bipolar disorder
• Depression
• Schizophrenia

CACNA1C encodes the L-type calcium channel (LTCC) Cav1.2. LTCCs are required for normal dopaminergic neurotransmission between the VTA and the nucleus accumbens. Reduced CACNA1C levels impair the function of the mesolimbic dopamine system: In mice with CACNA1C haploinsufficiency, sub-second frequency dopamine release was insensitive to DAT inhibition. Constitutive CACNA1C haploinsufficiency resulted in reduced hyperkinesia following acute administration of DAT-specific stimulants. The locomotor sensitization of these mice to the DAT antagonist GBR12909 was weaker than in wild-type mice. Sensitization to GBR12909 was selectively attenuated in the VTA, but not in the nucleus accumbens, in mice with reduced CACNA1C. CACNA1C appears to modify the presynaptic function of the mesolimbic dopamine system. Since the identified single-nucleotide polymorphisms are located in an intronic (non-coding, “in-tron”) region of CACNA1C, the genetic influence on risk is likely mediated through altered CACNA1C levels in specific brain regions.¹⁰⁰ Hyperkinesia induced by high doses of d-amphetamine is attenuated in mice lacking a copy of CACNA1C .¹⁰¹

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.98. CACNB2, Calcium Voltage-Gated Channel Auxiliary Subunit Beta 2¶

Other names: CACNLB2, MYSB, Voltage-Dependent L-Type Calcium Channel Subunit Beta-2, Calcium Channel, Voltage-Dependent, Beta 2 Subunit

CACNB2 mediates the entry of calcium ions into cells. CACNB2 contributes to the function of the calcium channel by increasing the peak calcium current, shifting the voltage dependence of activation and inactivation, modulating G-protein inhibition, and controlling the membrane targeting of the alpha-1 subunit.¹⁰²
CACNB2 is associated with:¹⁰³¹⁰⁴

• High blood pressure
  • rs4373814-G/C35
  • rs12258967-G/C46
  • rs11014166-A/T81
• bipolar disorder
• Brugada syndrome 4
• major depressive disorder
• Schizophrenia
• Lambert-Eaton myasthenic syndrome
• Autism Spectrum Disorder
• ADHD
• Heart failure
• sudden cardiac death

Related signal paths:

• sensory processing of sound
• CREB signaling pathway

Stimulation of L-type calcium channels increases tyrosine hydroxylase And dopamine in ventral midbrain cells.¹⁰⁵ In addition, there is considerable further evidence that L-type calcium channels influence dopamine levels.^106107108109

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰
In addition to ADHD, mutations in the CACNB2 gene have also been linked to:¹¹⁰

1.105. MAN2A2, Alpha Mannosidase Class 2A Member 2¶

Other names: MANA2X; Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase; Alpha-mannosidase IIx; Alpha-mannosidase 2x; EC 3.2.1.114; Alpha-mannosidase II, Member 1

The MAN2A2 protein mediates alpha-mannosidase activity. It is involved in N-glycan processing, by catalyzing the first step in the biosynthesis of complex N-glycans. MAN2A2 is thus involved in protein deglycosylation. It is thought to be an integral component of the membrane and to be active in the Golgi membrane.
Glycosylases are a group of enzymes that includes glucosidases, mannosidases, and heparanases. There are two glucosidase subtypes (MAN2A1 and MAN2A2), both of which are found in the intestine. They hydrolyze terminal (1,4)-alpha-glucosidic bonds and (1,6)-beta-glucosidic bonds, thereby releasing alpha-glucose and beta-glucose.¹¹¹ MAN2A2 is expressed at relatively high levels—just like MAN2A2—presumably because these are required for complex N-glycans.¹¹²
MAN2A2 is associated with

• Abdominal obesity - Metabolic syndrome Quantitative Trait Locus 2
• Schizophrenia (not definitively diagnosed)¹¹²

MAN2A1-KO mice exhibit a deficiency of N-glycans on erythroid cells, anemia, and a late-onset autoimmune disease similar to systemic lupus erythematosus, but otherwise show no disorders.
MAN2A2-KO mice exhibit male infertility without any other disorders.
The deletion of either MAN2A1 or MAN2A2 alone results in relatively mild and organ-specific phenotypes.
In contrast, the simultaneous deletion of MAN2A1 and MAN2A2 results in perinatal lethality and a complete lack of complex N-glycans.¹¹²

A study identified MAN2A2 as one of the 51 most likely genetic candidates for ADHD.[^10]

2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

See monogenetic causes of ADHD

1.93. TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD¶

Other names: TAFII250, DYT3/TAF1, NSCL2, TAF2A, KAT4, BA2R, CCG1, CCGS, TAF1 RNA Polymerase II, TATA Box Binding Protein (TBP)-Associated Factor, 250 kDa, Transcription Initiation Factor TFIID Subunit 1, TBP-Associated Factor 250 kDa, Cell Cycle Gene 1 Protein, EC 2.7.11.1, TAF(II)250

TAF1 plays a special role in the expression of the dopamine transporter. Unlike most housekeeping genes, the DAT promoter lacks a TATA box. As a result, the initiation of DAT transcription may depend to a large extent on the composition of the TATA-box-binding protein (TBP), which is primarily regulated by histone acetylation. This unique genomic structure makes DAT susceptible to epigenetic regulation.¹¹⁶

The TAF1 protein:

• is the largest subunit and the core structure of the basal transcription factor complex TFIID.
• contains new N- and C-terminal Ser/Thr kinase domains that can autophosphorylate or transphosphorylate other transcription factors
• phosphorylates TP53 at ‘Thr-55’, leading to MDM2-mediated degradation of TP53
• phosphorylates GTF2A1 and GTF2F1 at Ser residues
• has DNA-binding activity
• essential for the progression of the G1 phase of the cell cycle
• exhibits histone acetyltransferase activity toward histones H3 and H4
• binds to core promoter sequences that include the transcription start site
• binds to activators and other transcription regulators, which affects the rate of transcription initiation
• contains two independent protein kinase domains at the N- and C-termini
• possesses acetyltransferase activity
• can act as a ubiquitin-activating/conjugating enzyme.
• regulates apoptotic pathways in synovial fibroblasts

Mutations in TAF1 lead to

• Dystonia 3, torsion, X-linked, a dystonia-parkinsonism disorder
• Intellectual Developmental Disorder, X-linked, Syndrome 33

OMIM: TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD

A study found a change in TAF1 expression in ADHD.¹¹⁷

1.366 Transferrin gene¶

See monogenetic causes of ADHD

Dopamine Metabolism¶

1.10. MAOA, Monoamine Oxidase A Gene (Chromosome Xp11.3) (x)¶

OMIM: Monoamine oxidase A gene, MAOA

MAO-A is a candidate for ADHD.¹

The MAO-A gene controls the production of the enzyme monoamine oxidase A. In a 2006 study, the MAO-A gene was identified as a candidate gene for ADHD with a p-value of 0.02.³
A specific variant of the MAO-A gene doubles the risk of aggression and antisocial behavior if the people with ADHD were themselves exposed to violence (or, more generally, intense stress) during childhood. It occurs more frequently in boys because men—unlike women—do not have a second copy of this gene that could mitigate the defect.
This MAO-A gene variant is also associated with ADHD. However, we consider this to be a comorbidity that, while it frequently occurs alongside ADHD-HI (but not ADHD-I), is not part of ADHD itself. Steinhausen takes a similar view regarding social behavior disorders,¹¹⁸ noting that they are the most common comorbidity. However, Steinhausen describes the comorbidity of social behavior disorders as a subtype of ADHD, a view we do not share due to the distinct genetic basis of the other conditions. Further evidence supporting a pure comorbidity and against an ADHD-HI subtype is that medications for aggression disorders and antisocial behavior are typically dopamine D2 receptor antagonists (antipsychotic medications), which reduce the effect of dopamine uptake at the postsynaptic neuron’s (inhibitory*) D2 receptor, whereas in ADHD, receptor affinity is generally assumed to be too low (see above).

A case report describes a boy with a new MAOA gene variant p.(Thr408Met) who has ADHD, motor coordination difficulties, a tendency to bite objects, developmental coordination disorder, and a speech sound disorder.¹¹⁹

1.11. MAOB, Monoamine Oxidase B Gene (Chromosome Xp11.4-p11.3)¶

MAO-B is a candidate for ADHD.¹

Unlike MAO-A inhibitors, MAO-B inhibitors have been shown to be ineffective in treating ADHD.¹²⁰

1.12. COMT, Catechol-O-Methyltransferase (Chromosome 22q11.21)¶

OMIM: Catechol-O-methyltransferase; COMT

COMT is a candidate gene for ADHD.¹

1.12.1. COMT Val158Val¶

The COMT gene variant Val158Val causes increased breakdown of dopamine and norepinephrine, leading to a dopamine deficiency in the PFC; however, this in turn can result in increased dopaminergic activity in the mesolimbic system.^{121122 123 124} .¹²⁵

1.12.2. COMT Met158Met¶

The COMT Met158 Met variant is associated with antisocial behavior in ADHD.¹²⁶

This could explain why, to the best of our knowledge, this genetic variant has been observed in ADHD only when it is accompanied by comorbid antisocial behavior, but not yet in ADHD in general. In addition, this genetic variant is associated with borderline personality disorder and—via increased dopaminergic activity in the mesolimbic system—with the positive symptoms of schizophrenia.
This gene variant directly impairs working memory, which in turn indirectly influences delay aversion and directly influences executive functions and attentional control, as well as—together with the latter—the processing of auditory stimuli, which is a prerequisite for language processing. Regarding the question of whether this COMT gene variant correlates with ADHD, there are more conflicting than supporting studies; however, these studies did not take working memory into account.¹²⁷
This genetic variant is also relevant in cases of antisocial behavior associated with ADHD, but not in cases of ADHD without antisocial behavior.¹²² However, to our understanding, antisocial behavior is a comorbid disorder and not part of ADHD.

1.12.3. COMT Val108/158 Met¶

The COMT Val108/158 Met polymorphism reduces the enzyme’s activity in the breakdown of dopamine to one-quarter. This variant correlates with a more focused and efficient cerebrovascular response during working memory tasks. ¹²⁸
This variant is not associated with ADHD, in which dopamine levels are too low, but with schizophrenia, in which dopamine levels in the synaptic cleft are elevated.

1.283. STS, STEROID SULFATASE¶

Steroid sulfatase catalyzes the breakdown of dopamine through sulfation. For more information, see Sulfation by Sulfotransferases In the article Dopamine Degradation.
Steroid sulfatase (STS) catalyzes the conversion of sulfated steroid precursors into their respective free steroids in the endoplasmic reticulum. This includes, among others,

• DHEA sulfate to DHEA
• Estrone sulfate to estrone
• Pregnenolone sulfate to pregnenolone
• Cholesterol sulfate to cholesterol

A steroid sulfatase deficiency therefore leads to a deficiency of these steroid hormones. Mice with a deficiency of the STS enzyme exhibit clear ADHD symptoms.¹²⁹¹³⁰ This appears to be accompanied by elevated serotonin levels in the hippocampus and increased motivation.¹³¹
The STS genetic disorder X-linked ichthyosis (steroid sulfatase deficiency) is associated with an increased risk of ADHD, ASD, and social communication disorders.¹³²
DHEAS and STS influence attention.¹³³ DHEAS administration improved performance on the five-choice serial reaction time task under conditions requiring high levels of attention, whereas STS inhibition impaired accuracy. No effects on baseline motor activity were observed.

The STS gene is a candidate gene for ADHD.¹³⁴¹³²

The STS polymorphisms at the 5’-end of the gene were significantly associated with ADHD¹³⁵

• rs2770112
• rs12861247

Dopamine Regulation¶

1.31. DRD1IP, Calcylon (Chromosome 10q26) (x)¶

Other names: Dopamine Receptor D1-Interacting Protein

Calcylon is involved in the regulation of the D1 receptor.¹³⁶

OMIM: Calcyon (CALY) gene / Dopamine Receptor D1-Interacting Protein; DRD1IP gene

CALY / DRD1IP is a candidate gene for ADHD.¹

1.78. MTHFR, 5,10-Methylenetetrahydrofolate Reductase¶

The enzyme methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylene-FH4 to 5-methyl-FH4 with the help of NAD(P)H. Since this process produces the methylating agent 5-methyl-FH4, MTHFR is essential for many metabolic pathways, including the breakdown of harmful homocysteine into methionine and bacterial methane production.
Humans express MTHFR in many types of tissue, from which the protein is released into the bloodstream. Variants and mutations in the MTHFR gene can lead to reduced—and, in rare cases, increased—MTHFR synthesis and activity. MTHFR deficiency can

• in pregnant women can cause neural tube defects such as spina bifida in newborns
• Cause homocystinuria
• Increase the risk of stroke
• Increase the risk of colorectal cancer.

Homocysteine reduces dopamine levels in the striatum.¹³⁷

OMIM: MTHFR (5,10-methylenetetrahydrofolate reductase)

The 1298A > C polymorphism of the MTHFR gene has been associated with an increased risk of ADHD, but the MTHFR 677 C > T polymorphism has not.¹³⁸

The MTHFR 1298A > C polymorphism is associated with elevated homocysteine levels, likely due to reduced homocysteine breakdown caused by this polymorphism.¹³⁹

ADHD is associated with elevated homocysteine levels (and reduced vitamin B12 levels).¹⁴⁰¹⁴¹
A B12 deficiency can raise homocysteine levels.¹⁴²

1.81. ARTN, Artemin; 1p34.1¶

ARTN (Artemin, Enovin, Neublastin) is a neurotrophic factor belonging to the family of glial cell line-derived neurotrophic factor (GDNF) ligands, a group of ligands within the TGF-beta superfamily of signaling molecules. ARTN promotes the survival of a number of peripheral neuronal populations and at least one population of dopaminergic CNS neurons. ARTN is frequently expressed near these neurons. ARTN is a ligand for the RET receptor and uses GFR-alpha 3 as a co-receptor. ARTN plays a role in axonal development.
ARTN is involved in the structural development and plasticity of various types of neurons, including the dopaminergic neurons of the ventral midbrain. ARTN plays an important role in the migration, proliferation, and differentiation of sympathetic neurons during development.

OMIM: ARTN, Artemin; 1p34.1

Increased expression and reduced methylation in ADHD.¹⁴³
Candidate genes in a GWAS study.¹⁴⁴

1.127. GPR139, Probable G-protein-coupled receptor 139¶

Other names: G(q)-coupled orphan receptor GPRg1, G-protein-coupled receptor PGR3

GPR139 is active in the plasma membrane. GPR139 is involved in the G protein-coupled receptor signaling pathway (particularly Gq/11 and, to a lesser extent, G12/13), the phospholipase C-activating G protein-coupled receptor signaling pathway, and signal transduction. GPR139 may play a role in motor activity, food intake, alcohol dependence, hyperalgesia, and phenylketonuria (PKU).
Endogenous agonists are likely the aromatic amino acids L-Trp and L-Phe, as well as ACTH/α-MSH-related peptides. GPR139 appears to increase cAMP levels and induce ERK phosphorylation.
GPR139 appears to form receptor heterodimers with the dopamine D2 receptor and to moderate D2 activation.¹⁴⁵

The GPR139 receptor is expressed almost exclusively in the brain, particularly in the ventrolateral region of the caudate putamen, the habenular nucleus, the zona incerta, and the medial mammillary nucleus; according to another source, it is found in the striatum,¹⁴⁶, thalamus, hypothalamus, pituitary gland, and the habenula of the CNS.¹⁴⁵

GPR139 appears to be associated with:¹⁴⁵

• Schizophrenia
• ADHD and symptoms of inattention
• Depression
• fetal development

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.279. FOXP2¶

A substitution of two amino acids (T303N, N325S) in the FOXP2 transcription factor in mice resulted in reduced dopamine levels in these mice in:¹⁴⁷

• Nucleus accumbens
• Frontal cortex
• Cerebellum
• Putamen and caudate nucleus
• Globus pallidus

A meta-analysis of GWAS studies (k = 12, n = 55,374) found FOXP2 to be associated with ADHD.¹⁴⁸ This is consistent with the results from one (n = 1,262) of two arms of an earlier study.¹⁴⁹
FOXP2 is also associated with a severe language disorder.¹⁵⁰ According to this study, FOXP2 is involved in the development of corticostriatal and olivocerebellar circuits that play a role in motor control.

1.303. NR4A2, NURR1, Nuclear Receptor Subfamily 4 Group A Member 2¶

Other names: TINUR; NOT; HZF-3; RNR1; Transcriptionally Inducible Nuclear Receptor; Immediate-Early Response Protein NOT; Orphan Nuclear Receptor NURR1; Transcriptionally Inducible Nuclear Receptor-Related; NGFI-B/Nur77 Beta-Type Transcription Factor Homolog; Nuclear Receptor Subfamily 4, Group A, Member 2; Nur-Related Protein-1, Human Homolog of 3 Intermediate-Early Receptor Protein; Orphan Nuclear Receptor NR4A2; T-Cell Nuclear Receptor NOT; Nuclear Receptor-Related 1; IDLDP

NURR1 (NR4A2) is a transcription factor that regulates the dopamine signaling pathway and plays a crucial role in the differentiation, maturation, and maintenance of dopaminergic neurons in the midbrain. NURR1 is found in various regions of the central nervous system, including the cortex, hippocampus, brainstem, spinal cord, and olfactory bulb.¹⁵¹
Mice in which NURR1 was inactivated (NURR1-KO mice) developed hyperactivity and impulsivity, but not the other ADHD symptoms such as anxiety, problems with physical coordination, altered social behavior, or memory problems. Neither tyrosine hydroxylase (which limits catecholamine synthesis) nor dopamine levels were altered by NURR1 blockade. The hyperactivity caused by NURR1 inactivation could be reversed by methylphenidate.¹⁵² Nurr1-KO mice (Nurr1-/-) are unable to develop dopaminergic neurons in the midbrain and die shortly after birth. These mice exhibit impaired motor function and a significant loss of dopaminergic neurons in the SNpc and VTA. The expression of NURR1 in the dopaminergic neurons of the midbrain decreases with age, which coincides with the increased incidence of Parkinson’s disease.¹⁵¹
NURR1—in interaction with other factors—regulates the expression of TH, AADC, and VMAT2, which are essential for the synthesis, storage, and release of dopamine. Furthermore, NURR1 activates the transcription of the TH gene, thereby exerting a significant influence on dopamine synthesis.
NURR1 mutations and polymorphisms that cause either reduced expression or functional impairment have been associated with familial and sporadic Parkinson’s disease.¹⁵¹

The NR4A2 (NURR1) protein is a member of the steroid-thyroid hormone-retinoid receptor superfamily. NR4A2 is a transcription regulator that is important for the differentiation and maintenance of mesodiencephalic dopaminergic (mdDA) neurons during development. It is critical for the expression of a number of genes, such as SLC6A3, SLC18A2, TH, and DRD2, which are essential for the development of mdDA neurons. Mutations in this gene have been linked to disorders associated with dopaminergic dysfunction, including Parkinson’s disease, schizophrenia, and manic depression. Dysregulation of this gene may be associated with rheumatoid arthritis. ¹⁵³
NR4A2 is associated with

• Intellectual disability with language impairment
• early-onset dopa-responsive dystonia-parkinsonism
• Parkinson’s disease, late-onset

Paralog: NR4A3

1.122. CSMD1, CUB, and Sushi Multiple Domains 1¶

Other names: KIAA1890, PPP1R24, Protein Phosphatase 1, Regulatory Subunit 24, CUB and Sushi Domain-Containing Protein 1, CUB and Sushi Multiple Domains Protein 1

The CSMD1 protein is thought to be involved in learning and memory, the branching of the mammary glands during pregnancy, and the development of the reproductive organs. CSMD1 is likely an integral component of the membrane. CSMD1 is a potential suppressor of squamous cell carcinomas.¹⁵⁴

CSMD1 is associated with

• Autism
• Schizophrenia¹⁵⁵
• Anorexia nervosa¹⁵⁶

CSMD1 is part of the same signaling pathway as CREB3, PTPRD, and GAB1, and is involved in neuronal differentiation and the **dopamine pathway **.¹⁵⁶
CSMD1 plays a role in the ratio between dopamine and serotonin metabolites In cerebrospinal fluid.¹⁵⁷
CSMD1: c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) have been identified as candidate genes for Parkinson’s disease , which is also caused by dopamine dysfunction.¹⁵⁸

A study identified CSMD1 as one of the 51 most likely candidate genes for ADHD.¹⁰ Another study identified CSMD1 (variant rs6559123) as one of the 20 most likely candidate genes among 96 ADHD candidate genes.¹⁵⁹

Potassium channels influence dopamine¶

The function of potassium channels can influence dopaminergic tone. Therefore, potassium channels may be involved in the development of ADHD, as well as schizophrenia and ASD.^160161162163

1.85. KCNJ6, Potassium Inwardly Rectifying Channel Subfamily J Member 6¶

Other names: GIRK2; KATP2; BIR1; G Protein-Activated Inward Rectifier Potassium Channel 2; HiGIRK2; KCNJ7; Inward Rectifier K(+) Channel Kir3.2; Kir3.2; GIRK-2; KATP-2; Potassium Inwardly-Rectifying Channel, Subfamily J, Member 6; Potassium Channel, Inwardly Rectifying Subfamily J, Member 6; Potassium Channel, Inwardly Rectifying Subfamily J, Member 6; Potassium Voltage-Gated Channel Subfamily J Member 6; Inward Rectifier Potassium Channel KIR3.2; KIR3.2; KPLBS

KCNJ6 is a member of the family of G-protein-coupled inwardly rectifying potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; when extracellular potassium increases, the voltage range at which the channel opens shifts toward more positive voltages. The inward rectification is primarily due to the blocking of the outward current by intracellular magnesium. These proteins modulate many physiological processes, including heart rate in cardiac cells and synaptic activity in neuronal cells, through the stimulation of G-protein-coupled receptors. The potassium channel KCNJ6 may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting via G-protein-coupled receptors.

GeneCards Summary for the KCNJ6 Gene
KCNJ6 (Potassium Inwardly Rectifying Channel Subfamily J Member 6) is a protein-coding gene. Among the diseases associated with
KCNJ6 is associated with

• Keppen-Lubinsky syndrome (generalized lipodystrophy, progeroid features, and severe intellectual disability syndrome)
  • rare disease (less than 1 per 1,000,000)
  • severe developmental delay
  • Facial dysmorphism
  • intellectual disability
• Epilepsy
• ADHD

Related signal paths:

• Potassium channels
• Progeria-associated lipodystrophy
• Activity of the inward-directed potassium channel
• Activity of the G-protein-activated inward-opening potassium channel

Paralog: KCNJ5

OMIM: KCNJ6, POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 6

KCNJ6 regulates the excitability of dopaminergic neurons and is expressed in brain regions involved in ADHD.
KCNJ6 rs7275707 is associated with ADHD in children and correlates with increased reward dependence.
Both KCNJ6 rs7275707 and KCNJ6 rs6517442 influenced EEG activity during the N-back task in ADHD.
KCNJ6 rs6517442 influenced the activation of the ventral striatum during reward anticipation.¹⁶⁰

1.67. DPP10, Dipeptidyl Peptidase-Like 10 (Chromosome 2q14.1)¶

Other names: DPRP3; DPL2; DPPY; Dipeptidyl Peptidase IV-Related Protein 3; Dipeptidyl Peptidase-Like Protein; Dipeptidyl Peptidase 10 (Inactive); Inactive Dipeptidyl Peptidase 10; Dipeptidyl Peptidase X; DPRP-3; DPP X; Dipeptidyl Peptidase 10 (Non-Functional); Dipeptidyl Peptidase 10; Dipeptidyl Peptidase 10; Dipeptidyl Peptidase 10; KIAA1492

The DPP10 protein is a single-pass type II membrane protein belonging to the S9B family within the SC clan of serine proteases. It appears to have no detectable protease activity, which is most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds to specific voltage-gated potassium channels and alters their expression and biophysical properties.
DPP10 mutations are associated with

• Asthma
• Autism Spectrum Disorders

OMIM: DIPEPTIDYL PEPTIDASE X; DPP10

DPP10 is associated with ADHD.²⁰, SNP: rs272000 116372265; Within 50 kb downstream of DPP10 with p: 9.10E−06¹⁶⁴ One study found a correlation with ADHD for the variant cg19651219, but not for the variants cg22670147, cg19651219, cg24654266, cg21322022, cg00089091, or cg19211931.¹⁶¹

1.268. KCNC2, Potassium Voltage-Gated Channel Subfamily C Member 2¶

Other names: Potassium Channel, Voltage-Gated Shaw-Related Subfamily C, Member 2; Potassium Voltage-Gated Channel, Shaw-Related Subfamily, Member 2; Voltage-Gated Potassium Channel Kv3.2; Shaw-Like Potassium Channel; Kv3.2; DEE103; KV3.2

The KCNC2 protein belongs to the class of delayed-rectifying channel proteins and is an integral membrane protein that mediates the voltage-dependent permeability of potassium ions in excitable membranes. Due to its sequence similarity, this gene resembles the Shaw subfamily of the Shaker gene family in Drosophila.
KCNC2 is associated with

• Developmental and Epileptic Encephalopathy 103
• extratemporal epilepsy

Related signaling pathways:

• Integration of energy metabolism
• Potassium channels / ion channel activity
• delayed rectifier potassium channel activity

Paralog: KCNC4

KCNC2 contributes to the regulation of rapid action potential repolarization and to sustained high-frequency firing in neurons of the central nervous system. Homotetrameric channels mediate delayed-rectifying voltage-dependent potassium currents that are rapidly activated and slowly inactivated at high-threshold voltages. They form tetrameric channels through which potassium ions flow in accordance with their electrochemical gradient. The channel switches between open and closed conformations in response to the voltage difference across the membrane. It can form functional homotetrameric and heterotetrameric channels containing variable proportions of KCNC1 and possibly other family members; the channel properties depend on the type of alpha subunits that make up the channel. The channel properties can be modulated either through association with additional subunits such as KCNE1, KCNE2, or KCNE3, or indirectly by nitric oxide (NO) via a cGMP- and PKG-mediated signaling cascade that slows the activation and deactivation of delayed-rectification potassium channels (By similarity). Contributes to the high-frequency firing of sustained bursts of very short action potentials in retinal ganglion cells, thalamocortical and suprachiasmatic (SCN) neurons, as well as in hippocampal and neocortical interneurons. The frequency of the sustained maximum action potential in inhibitory interneurons of the hippocampus is negatively modulated by activation of the histamine H2 receptor, which is dependent on phosphorylation by cAMP and protein kinases (PKA). It plays a role in maintaining the reliability of synaptic transmission in neocortical GABAergic interneurons by inducing repolarization of the action potential (AP) at the nerve terminals, thereby reducing the spike-evoked calcium influx and the release of GABA neurotransmitters. Essential for the synchronization of gamma oscillations over long distances in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potentials in neurons of the suprachiasmatic nucleus (SCN) in a light-dependent manner.¹⁶⁵

A study identified KCNC2 (variant rs17114649) as one of 96 ADHD candidate genes.¹⁵⁹

1.100. DPP6, Dipeptidyl-Aminopeptidase-Like Protein 6¶

Other names: Dipeptidyl Peptidase-Like 6, DPPX, DPL1, Dipeptidyl Aminopeptidase-Like Protein 6, Dipeptidyl Peptidase VI, Dipeptidyl Peptidase 6, Dipeptidyl Peptidase 6, DPP VI

DPP6 is a single-pass type II membrane protein from the S9B family in the SC clan of serine proteases. DPP6 has no detectable protease activity, which is most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds to specific voltage-gated potassium channels and alters their expression and biophysical properties.¹⁶⁶
DPP6

• promotes the cell surface expression of the KCND2 potassium channel
• modulates the activity and gating properties of the KCND2 potassium channel
• has no dipeptidylaminopeptidase activity

Diseases associated with DPP6 include:

• Intellectual Developmental Disorder, Autosomal Dominant 33
• Paroxysmal Familial Ventricular Fibrillation, 2.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.64. KCNC1 (Chromosome 11p15.1)¶

Other names: POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 1

The KCNC1 protein is a member of a family of integral membrane proteins that mediate the voltage-dependent permeability of potassium ions in excitable membranes. KCNC1 influences the dopamine-DARPP32 feedback loop on the cAMP pathway.¹⁶⁷
Alternative splicing appears to result in two isoforms with different C-termini.
Diseases associated with KCNC1 include epilepsy, progressive myoclonic disorder 7, and spinocerebellar ataxia 13.

OMIM: POTASSIUM CHANNEL, VOLTAGE-GATED, SHAW-RELATED SUBFAMILY, MEMBER 1

• SNP: rs3893215 Position: 7721406; In the intron of KCNC1¹⁶⁴
  p: 2.56E−05

1.65. KCNIP4, Potassium Voltage-Gated Channel Interacting Protein 4 (Chromosome 4p15.3-p15.2)¶

Other names: KCHIP4; CALP; A-Type Potassium Channel Modulatory Protein 4; Kv Channel Interacting Protein 4; Kv Channel-Interacting Protein 4; Calsenilin-Like Protein; MGC44947; Potassium Channel-Interacting Protein 4; KChIP4

The KCNIP4 protein is a member of the family of voltage-gated potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the recoverin branch of the EF-hand superfamily. Members of the KCNIP family are small calcium-binding proteins with EF-hand-like domains that differ from one another at the N-terminus. They are integral subunits of native Kv4 channel complexes. They can regulate A-type currents and, consequently, neuronal excitability in response to changes in intracellular calcium. KCNIP4 also interacts with presenilin. KCNIP4 is involved in cardiac conduction, in the regulation of nuclear β-catenin signaling, and in the transcription of target genes.¹⁶⁸
KCNIP4 is associated with

• Synovial angioma
• congenital capillary malformations

OMIM: POTASSIUM CHANNEL-INTERACTING PROTEIN 4, KCNIP4

• SNP rs876477 Position: 20766026; intron of KCNIP4¹⁶⁴
  p: 2.69E−05

1.66. KCNIP1, Potassium Voltage-Gated Channel Interacting Protein 1¶

Other names: KCHIP1; A-Type Potassium Channel Modulatory Protein 1; Kv Channel Interacting Protein 1; Kv Channel-Interacting Protein 1; Vesicle APC-Binding Protein; VABP; Potassium Channel Interacting Protein 1; Potassium Channel-Interacting Protein 1; KChIP1

KCNIP1 is a member of the family of cytosolic voltage-gated potassium (Kv) channel interaction proteins (KCNIPs), which belong to the family of neuronal calcium sensors (NCS) among calcium-binding EF-hand proteins. They associate with Kv4-alpha subunits to form native Kv4 channel complexes. KCNIP1 can regulate fast-inactivating (A-type) currents and, thereby, neuronal membrane excitability in response to changes in intracellular calcium concentration. KCNIP1 regulates channel density, inactivation kinetics, and the rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, KCNIP1 modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents. KCNIP1 increases the presence of KCND2 at the cell surface.¹⁶⁹
KCNIP1 is associated with

• Epilepsy, idiopathic generalized
• Hypertension, diastolic

Related signal paths:

• cardiac conduction
• Calcium ion binding
• Protein N-terminus binding

Paralog: KCNIP4

OMIM: POTASSIUM CHANNEL-INTERACTING PROTEIN 1; KCNIP1

The SNP rs1541665, located at position 170075495 in the intron of KCNIP1, is associated with ADHD.¹⁶⁴¹⁷⁰

1.256. ALG10, ALG10 Alpha-1,2-Glucosyltransferase¶

Other names: ALG10A; DIE2; Dolichyl-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dolichol alpha-1,2-glucosyltransferase; Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol Alpha-1,2-Glucosyltransferase; Asparagine-Linked Glycosylation Protein 10 Homolog A; Alpha-1,2-Glucosyltransferase ALG10-A; Alpha-2-Glucosyltransferase ALG10-A; FLJ14751; Asparagine-Linked Glycosylation 10, Alpha-1,2-Glucosyltransferase Homolog (S. pombe); Asparagine-Linked Glycosylation 10, Alpha-1,2-Glucosyltransferase Homolog (Yeast); Asparagine-Linked Glycosylation 10 Homolog (Yeast, Alpha-1,2-Glucosyltransferase); Asparagine-Linked Glycosylation 10, Alpha-1,2-Glucosyltransferase Homolog; Derepression of ITR1 Expression 2 Homolog (S. cerevisiae); Derepression of ITR1 Expression 2 Homolog; Potassium Channel Regulator 1; Alpha2-Glucosyltransferase; EC 2.4.1.256; EC 2.4.1.16; EC 2.4.1; KCR1

ALG10 is a membrane-associated protein that attaches the third glucose residue to the lipid-bound oligosaccharide precursor for N-linked glycosylation. In this process, ALG10 transfers the terminal glucose from dolichyl phosphate glucose (Dol-P-Glc) to the lipid-bound oligosaccharide Glc2Man9GlcNAc(2)-PP-Dol. The rat protein homolog has been shown to specifically modulate the gating function of the rat neuronal Ether-a-go-go (EAG) potassium ion channel.¹⁷¹
ALG10 is associated with

• Long-QT syndrome type 2
• Toxic myocarditis

Related signaling pathways:

• Transport to the Golgi apparatus and subsequent modification
• Initial stage of N-glycosylation of proteins (eukaryotic)

Paralog: ALG10B

A study identified ALG10 (rs1843014) as one of 96 ADHD candidate genes.¹⁵⁹

Other dopaminergic influences¶

1.30. ADGRL3, LPHN3, Latrophilin-3 (Chromosome 4q13.1)¶

Other names: ADHESION G PROTEIN-COUPLED RECEPTOR L3; Adhesion G Protein-Coupled Receptor L3; LEC3; KIAA0768; LPHN3; Calcium-Independent Alpha-Latrotoxin Receptor 3; Latrophilin-3; Latrophilin Homolog 3 (Cow); Latrophilin 3; Lectomedin 3; Lectomedin-3; CIRL-3; CIRL3; CL3

ADGRL3 is a G-protein-coupled receptor belonging to the adhesion receptor subfamily. ADGRL3 regulates synaptic function and plays a role in maintaining brain regions involved in motor activity, attention, and spatial and route memory.
Latrophilins may play a role in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS domain (G-protein-coupled receptor proteolytic cleavage site) resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit showing significant similarity to the secretin/calcitonin family of GPCRs) to become noncovalently bound to the cell membrane. ADGRL3 plays a role in cell-cell adhesion and neuronal guidance through its interactions with FLRT2 and FLRT3, which are expressed on the surface of neighboring cells. ADGRL3 plays a role in the development of glutamatergic synapses in the cortex. ADGRL3 is important in determining the connectivity rates between principal neurons in the cortex.¹⁷²
ADGRL3 is associated with

• Sialuria
• Amed syndrome, digenic

Related signaling pathways:

• GPCRs, Class B secretin-like
• GPCRs, others
• G-protein-coupled receptor activity
• Carbohydrate binding

Paralog: ADGRL2

OMIM: Latrophilin-3 (LPHN3) gene / ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3 gene

ADGRL3 (LPHN3)-KO mice serve as an animal model for ADHD.¹⁷³
ADGRL3-KO mice show:¹⁷⁴

• Hyperactivity in a new environment and when on cocaine
  - elevated dopamine and serotonin levels in the striatum
• no inattention¹⁷⁵
• altered dopamine and serotonin receptor expression
  - altered expression of DAT,, calcium signaling, and other cell adhesion proteins.

Compared to WT rats, ADGRL3-KO rats showed:

• unchanged dopamine, norepinephrine, serotonin, or other important metabolites in the striatum, hippocampus, or PFC¹⁷⁶
• Increased levels of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the striatum¹⁷⁶
  • This could be an indication of higher levels of dopamine and/or norepinephrine in the striatum¹⁷⁶
• an increased density of DAT in the striatum¹⁷⁶
• reduced total phasic dopamine release and DAT in the nucleus accumbens and the mPFC¹⁷⁷
• hypodopaminergic signaling in the ventral stream of the NAcc-mPFC, which is associated with motivation and goal-directed behavior¹⁷⁷

Increased phasic dopamine release in the neostriatum may contribute to the hyperactive behavior of ADGRL3-KO rats¹⁷⁷
Reduced phasic dopamine release in the nucleus accumbens (¹⁷⁷ ) could explain the impulsivity problems compared to WTs.^178179175

ADGRL3 is involved in regulating the amount, duration, and frequency of dopamine release in the neostriatum (caudate-putamen).¹⁷⁴

• exhibits saturated phasic dopamine neurotransmission in the neostriatum (caudate nucleus–putamen; [91]), which may be partly responsible for the downregulation of D1 receptors [28].

ADGRL3 is a candidate gene for ADHD.^{1180 181 182} It is most commonly found in the prefrontal cortex (PFC), caudate nucleus, amygdala, and cerebellum, all of which play an important role in ADHD.¹⁸³
ADGRL3 expression peaks during the early stages of neurodevelopment and is found primarily in glutamatergic neurons within cone-shaped structures, suggesting a role in neurite outgrowth and the development of glutamatergic synapses. rs1397547 correlates with significantly increased ADGRL3 transcription in early stages of neurodevelopment.¹⁸⁴
ADGRL3 binds to Gαi1, Gαi2, Gαs, Gαq, and Gα13. In particular, genetic variants that result in impaired Gα13 binding appear to be relevant in ADHD.¹⁸⁵ SNPs in ADGRL3 showed a correlation with the severity of ADHD symptoms and a potential pleiotropic effect on various aspects of ADHD severity.¹⁸⁶ ADGRL3 gene variants interact with gene variants on chromosome 11q (in a region spanning the NCAM1, TTC12, ANKK1, and DRD2 genes) and drastically increase the risk of ADHD and its severity in young children.^{187188 183 180} A combination of ADGRL3 rs65511665 and a haplotype in 11q increases the risk of ADHD by a factor of 2.5.¹⁸⁹
ADGRL3 rs2345039 is a predictor of ADHD-C with symptoms persisting into adolescence.¹⁸⁷
ADGRL3 rs65511665 is associated with an increased prevalence of ADHD and a subtype with high comorbidity with conduct disorder.¹⁸³¹⁹⁰ ADGRL3 rs65511665 is associated with response to stimulants.¹⁸³¹⁹⁰

1.296. SORCS3, Sortilin-Related VPS10 Domain-Containing Receptor 3¶

Other names: KIAA1059; SORCS; VPS10 Domain-Containing Receptor SorCS3; Sortilin-Related VPS10 Domain-Containing Receptor 3; VPS10 Domain Receptor Protein SORCS 3 (SORCS3)

SORCS3 is a type I receptor transmembrane protein belonging to the vacuolar protein sorting 10 (VPS10) receptor family. Proteins in this family are characterized by a VPS10 domain at the N-terminus. The N-terminal segment of this domain contains a consensus motif for processing by proprotein convertase, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The VPS-10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adapter molecules. The transcript is highly expressed in the brain.¹⁹¹
SorCS is expressed in a unique, transient, and dynamic pattern in regions where cells are proliferating, as well as in areas containing already differentiated cells, including the cortex, the VTA, and the globus pallidus. SorCS expression begins with the onset of dopaminergic neuron differentiation and declines to low levels in adulthood. The VTA projects dopaminergic projections to the basal ganglia, the amygdala, and the cerebral and piriform cortices. These regions are also characterized by the presence of dopaminergic neurons and express SorCS. This suggests a possible role for SorCS in the development of dopaminergic pathways.¹⁹²
SORCS3 is associated with

• ADHD
• Alzheimer’s
  • Knocking out the SORCS3 gene in cell cultures led to increased processing of the amyloid precursor protein

Related signal paths:

• Neuropeptide receptor activity

Paralog: SORCS1

This gene was identified as a candidate for ADHD in a large-scale GWAS.¹⁹³¹⁹⁴

1.76. DIRAS2; DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2 (Chromosome 9q22.2)¶

The DIRAS2 (Di-Ras2) protein belongs to a branch of the functionally diverse Ras superfamily of monomeric GTPases. Ras proteins play a role in cell morphogenesis and neurogenesis.
The effector mechanisms of DIRAS2 are largely unknown. Unlike other Ras kinases, DIRAS2 does not activate MAP kinase, phosphoinositide 3-kinase, or the AKT signaling pathway. DIRAS2 exhibits low GTPase activity and is predominantly present in the GTP-bound form. It is even unclear whether DIRAS2 is regulated by GTP binding at all.¹⁹⁵ DIRAS2 is expressed at particularly high levels in lower raphe serotonin neurons¹⁹⁶, which could indicate a role in the regulation of the caudal serotonergic system.
DIRAS2 inhibited colorectal cancer cell proliferation and influenced the expression of cell cycle proteins. DIRAS2 blocked the NF-κB signaling pathways, leading to a G0/G1 arrest. DIRAS2 interacted with the non-ATPase regulatory subunit 2 of the 26S proteasome (PSMD2), which facilitates the proteasome-mediated degradation of DIRAS2. DIRAS2 is degraded by PSMD2 via the proteasome. DIRAS2 inhibited the nuclear expression of P65 in both RKO and HT29 cells.¹⁹⁷ DIRAS2 reduced the ability of SmgGDS (a chaperone protein and guanine nucleotide exchange factor, RAP1GDS1), to interact with the RNA polymerase I transcription factor Upstream Binding Factor (UBF), localize to the nucleolus, and act as a tumor suppressor.¹⁹⁸

DIRAS2 is expressed in the human brain primarily in the hippocampus, PFC, ACC, and amygdala.¹⁹⁵¹⁹⁹ During brain development in mice, DIRAS2 levels rise sharply from the prenatal to the late postnatal stage. Diras2 is expressed in glutamatergic and catecholaminergic neurons.¹⁹⁹

DIRAS2 acts as a tumor suppressor gene in cutaneous melanoma by inhibiting Wnt/β-catenin signaling. It is also associated with immune infiltration in cutaneous melanoma (²⁰⁰ ), papillary thyroid microcarcinoma (²⁰¹ ), and colorectal cancer (the most common gastrointestinal cancer) ( ).¹⁹⁷

OMIM: DIRAS FAMILY, GTP-BINDING RAS-LIKE PROTEIN 2; DIRAS2

DIRAS2 blocks the action of NF-κB.¹⁹⁷
This could represent a pathway to dopamine, since NF-κB regulates the expression of the striatal dopamine D2 receptor (D2R) and the adenosine A2A receptor (A2AAR) in the striatum. NF-κB p50 subunit knockout (NF-κB p50 KO) mice exhibited the following in the striatum:²⁰²

• more A2AAR
• lower A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperon binding
• elevated levels of G(alphaolf) and G(alphas) proteins
  • These transmit A2AAR signals
    G(alpha1)-protein with reduced activity
    It transmits signals from A1AR and D2R

NF-κB p50 knockout mice exhibited increased motor activity in response to caffeine.

DIRAS2 is a candidate gene for ADHD.¹⁹⁹ The study found evidence of a correlation with ADHD in:¹⁹⁵

• A allele of rs1331503
• T allele of rs1412005
• Haplotype ACGCTT from Block 2 (consisting of the SNPs rs1331503, rs2297354, rs1331504, rs7848810, rs1412005, and rs689687)

DIRAS2 is associated not only with ADHD, but also with bipolar disorder and Parkinson’s disease. A cross-disorder analysis of all disorders combined (ADHD, bipolar disorder, and Parkinson’s disease) revealed a 13% increased risk for the rs1412005 T allele.¹⁹⁵
The association between ADHD and Parkinson’s disease could suggest that DIRAS2 influences the dopaminergic system.

1.90. TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1¶

The TLE1 protein is part of the beta-catenin-TCF complex. It is found in the cytosol and nucleoplasm.
TLE1:²⁰³

• enables identical protein-binding activity and transcriptional corepressor activity.
• binds to a number of transcription factors
• Inhibition of the “ “ by FOXA2 and by members of the CTNNB1 and TCF families in Wnt-signaling-mediated transcriptional activation
• Enhancement of FOXG1/BF-1- and HES1-mediated transcriptional repression
• Inhibition of signal transduction and expression of NF-kappa-B / kappa-B kinase
• Inhibition of anoikis
• influences the Notch signaling pathway during development
• affects RNA polymerase I promoter opening
• Coactivator for ESRRG

TLE1 is associated with the following diseases

• Core-binding factor in acute myeloid leukemia
• Glomerular tumor

TLE1 impaired NOD2 signaling and, consequently, NF-κB signaling in the liver.²⁰⁴
This could represent a pathway to dopamine, since NF-κB regulates the expression of the striatal dopamine D2 receptor (D2R) and the adenosine A2A receptor (A2AAR) in the striatum. NF-κB p50 subunit knockout (NF-κB p50 KO) mice exhibited the following in the striatum:²⁰²

• more A2AAR
• lower A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperon binding
• elevated levels of G(alphaolf) and G(alphas) proteins
  • These transmit A2AAR signals
    G(alpha1)-protein with reduced activity
    It transmits signals from A1AR and D2R

NF-κB p50 knockout mice exhibited increased motor activity in response to caffeine.

OMIM: TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1

A study found altered expression of TLE1 in ADHD.¹¹⁷ TLE1 had already been identified as a candidate gene for ADHD in another study.²⁰⁵

1.125. FERMT3, FERM Domain-Containing Kindlin 3¶

Other names: KIND3, MIG2B, URP2, UNC112C, UNC-112 Related Protein 2, Fermitin Family Homolog 3, Unc-112-Related Protein 2

The FERMT3 protein is a member of the Kindlin protein family, which mediates protein-protein interactions during integrin activation and thereby plays a role in cell adhesion, migration, differentiation, and proliferation. FERMT3 plays a key role in the regulation of hemostasis and thrombosis. FERMT3 contributes to the maintenance of the erythrocyte membrane skeleton and plays a central role in cell adhesion in hematopoietic cells. FERMT3 acts by activating integrin beta-1-3 (ITGB1, ITGB2, and ITGB3). FERMT3 is required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells, as well as for the activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs). Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.²⁰⁶ Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages, and upregulation of beta-2 integrins in all major arterial beds.²⁰⁷
FERMT3 is associated with

• Leukocyte adhesion deficiency, type III
• Kindler syndrome

Inhibition of NF-kappa-B could represent a pathway to dopamine, since NF-kappa-B regulates the expression of the striatal dopamine D2 receptor (D2R) and the adenosine A2A receptor (A2AAR) in the striatum. NF-kappaB p50 subunit KO mice (NF-kappaB p50 KO mice) exhibited the following in the striatum:²⁰²

• more A2AAR
• lower A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperon binding
• elevated levels of G(alphaolf) and G(alphas) proteins
  • These transmit A2AAR signals
    G(alpha1)-protein with reduced activity
    It transmits signals from A1AR and D2R

NF-κB p50 knockout mice exhibited increased motor activity in response to caffeine.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.82. GLI1; PPD1; GLI Family Zinc Finger 1¶

Other names: GLI; Glioma-Associated Oncogene Homolog 1 (zinc finger protein); Zinc Finger Protein GLI1; Oncogene GLI; Glioma-Associated Oncogene Family Zinc Finger 1; GLI-Kruppel Family Member GLI1; Glioma-Associated Oncogene 1; Glioma-Associated Oncogene; PAPA8; PPD1

The GLI1 protein is a member of the Kruppel family of zinc-finger proteins. GLI1 acts as a transcription factor, is activated by the Sonic Hedgehog signaling cascade, and regulates stem cell proliferation. GLI1 is an effector molecule of the Hedgehog (Hh) signaling pathway. The activity and nuclear localization of GLI1 are negatively regulated by p53 in an inhibitory loop.²⁰⁸
GLI1 is associated with

• Polydactyly, postaxial, type A8
• Polydactyly, preaxial type I

Related signal paths:

• dopaminergic neurogenesis
• GPER1 signal transduction
• Chromatin binding
• Microtubule binding

The timing of Gli1 and Sonic Hedgehog expression distinguishes dopamine neurons in the midbrain.²⁰⁹ Gli1 protects nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration in Parkinson’s disease models.²¹⁰

Paralog: GLI2

GLI1 binds to the DNA consensus sequence 5’-GACCACCCA-3’. GLI1 regulates the transcription of specific genes during normal development. GLI1 plays a role in craniofacial and digital development, as well as in the development of the central nervous system and the gastrointestinal tract. GLI1 mediates SHH signaling. GLI1 plays a role in cell proliferation and differentiation through its role in SHH signaling.
[Isoform 2]: Acts as a transcription activator, but activates a different set of genes than isoform 1. Unlike isoform 1, isoform 2 activates the expression of CD24. Isoform 2 mediates SHH signaling and promotes the migration of cancer cells.

A study found increased expression and reduced methylation of GLI2 in ADHD.¹⁴³

1.307. DGKH; Diacylglycerol Kinase Eta¶

Other names: DGKeta; Diglyceride Kinase Eta; DAG Kinase Eta; EC 2.7.1.107; DGK-Eta; diacylglycerol kinase η

The DGKH protein is a member of the diacylglycerol kinase (DGK) enzyme family. Diacylglycerol kinases (DGKs) are a group of ten enzymes that metabolize 1,2-diacylglycerol (DAG) to phosphatidic acid (PA). They all contain a conserved C’-terminal catalytic domain and two cysteine-rich Zn²⁺-finger motifs with different regulatory domains. Diacylglycerol kinases (DGKs) are involved in regulating intracellular concentrations of diacylglycerol and phosphatidic acid. DGKH likely acts as a central switch between the signaling pathways activated by diacylglycerol and phosphatidic acid, which have different cellular targets and opposing effects in numerous biological processes. DGKH plays a key role in promoting cell growth. DGKH activates the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway, which is induced by EGF. DGKH regulates the recruitment of RAF1 and BRAF from the cytoplasm to the membranes and their heterodimerization.²¹¹
DGKH is affiliated with

• Bipolar Disorder
• Nephrolithiasis

Related signal paths:

• downstream GPCR signaling
• Response to elevated cytosolic Ca2+ in platelets
• NAD+ kinase activity
• Diacylglycerol kinase activity

DGKH expression increases during mouse brain development, suggesting a possible role for this kinase in late developmental stages. Immunostaining revealed strong DGKH expression in the hippocampus and cerebellum of mice and in the striatum of humans .

In DGKH-KO mice, dopamine and the phosphorylated dopamine transporter are elevated.²¹²

Hains and Arnsten describe an effect of DGKH on stress regulation. Excessive dopaminergic D1 receptor stimulation impairs prefrontal function via intracellular cAMP signaling, leading to a disruption of prefrontal networks, while excessive noradrenergic stimulation of alpha-1 receptors impairs prefrontal function via intracellular phosphatidylinositol protein kinase C signaling. DISC1, RGS4, and DGKH normally function to inhibit intracellular phosphatidylinositol protein kinase C signaling and thus act as brakes on these intracellular signaling pathways. Mutations that lead to the loss of proper function of these genes are likely to weaken the endogenous regulation of these signaling pathways, which may explain the susceptibility to stress and the severe loss of PFC regulation of behavior, cognition, and emotion (including cognitive impairments, disinhibition, and impaired working memory) in the disorders associated with these gene mutations.²¹³

Paralog: DGKD

A DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT, was associated with ADHD in adults, bipolar disorder (rs1170169 and rs9525580), and depression, while the complementary AGC haplotype had a protective effect.²¹⁴ One study found no evidence of gene-environment interactions related to rs994856/rs9525580/rs9525584 GAT in ADHD.²¹⁵

1.101. EMP2, Epithelial Membrane Protein 2¶

Other names: XMP, Protein XMP, EMP-2

EMP2 is a tetraspan protein of the PMP22/EMP family. EMP2 regulates the composition of the cell membrane. It influences²¹⁶

• Endocytosis
• Cell signaling
• Cell proliferation
• Cell migration
• Cell adhesion
• Cell death
• Cholesterol homeostasis
• Albumin excretion in the urine
• Embryo implantation
• promotes angiogenesis and vasculogenesis by inducing VEGFA via an HIF1A-dependent pathway
• inhibits caveolin-1 by increasing lysosomal degradation
• activates PTK2 and thereby regulates focal adhesion density, F-actin conformation, and cell adhesion
• modulates the function of certain integrin isomers in the plasma membrane
• regulates the surface expression of MHC1 and ICAM1
• EMP2 deficiency (such as in EMP2-KO mice) alters placental angiogenesis and mimics features of human placental insufficiency.²¹⁷ This can trigger oxygen deprivation. Hypoxia, in turn, is known to cause changes in the dopamine system. For example, oxygen deprivation during birth is a possible cause of ADHD.

EMP2 is associated with the following diseases

• nephrotic syndrome
• Genetic steroid-resistant nephrotic syndrome

Related paths:

• Protein kinase binding
• Kinase binding

Paralog: PMP22

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.317. SYN3, Synapsin III¶

Other names: Synapsin-3, CN28H9.2 (Synapsin III)

The SYN3 protein conforms to the domain model of the synapsin family, with domains A, C, and E showing the highest degree of conservation. The protein contains a unique domain J, located between domains C and E. Given the localization of this gene at 22q12.3—a potential schizophrenia susceptibility locus—and the established neurobiological role of synapsins, this family member could represent a candidate gene for schizophrenia. The TIMP3 gene is located within an intron of this gene and is transcribed in the opposite direction.²¹⁸

SYN3 is associated with

• Sorsby-Fundus Dystrophy
• Fundus dystrophy

Related signal paths:

• Neurotransmitter release cycle
• Transmission via chemical synapses
• Synaptogenesis

Paralog: SYN2

Syn III regulates the earliest stages of dopaminergic neuron development in vertebrates and mammals. Polymorphisms in the synapsin III (Syn III) gene are associated with ADHD and influence the response to MPH. MPH can bind to SYN3. The observed SYN3 polymorphism appears to influence the occurrence of ADHD and the response to MPH by impairing BDNF-dependent development of dopaminergic neurons.²¹⁹

1.318. SYN1, Synapsin 1¶

Other names: Synapsin I, Synapsin-1, Brain Protein 4.1; MRX50; X-Linked Mental Retardation 50; Synapsin Ib; EPILX; SYN1a; SYN1b; SYNI

Synapsins encode neuronal phosphoproteins that bind to the cytoplasmic surface of synaptic vesicles. Synapsins are characterized by shared protein domains and are involved in synaptogenesis and the modulation of neurotransmitter release.
Synapsin-I (SYN1) is a presynaptic phosphoprotein that is critical for synaptogenesis and synaptic plasticity. SYN1 plays a role in the regulation of axonogenesis and synaptogenesis. The encoded protein serves as a substrate for several different protein kinases, and phosphorylation may play a role in the regulation of this protein within the nerve terminal.²²⁰

SYN1 is associated with:

• X-linked disorders characterized by primary neuronal degeneration, which primarily affect males.
  • Rett syndrome

A study of 31 individuals identified 22 different SYN1 variants.²²¹

Syn1 abnormalities correlate with:²²¹

• ASD or ADHD in 91% of people with ADHD
• Epilepsy in 82% of cases
  • primarily tonic-clonic or focal seizures with impaired consciousness
  • Reflex seizures are one of the most common clinical manifestations associated with SYN1
  • Trigger:
    • Contact with water (> 50%)
    • Rubbing with a towel
    • Fever
    • Brushing your teeth
    • Cutting fingernails
    • Falling asleep
    • Watching other people while they are showering or bathing
    • Hyperpnea
    • Emotions
    • Light
    • Stroboscope
    • Digestive problems
    • Bowel movements
• intellectual disability in 77% of cases
  • correlates with an early age of onset
• Developmental delay in 70% of cases

The molecular spectrum of SYN1 variants is diverse

• truncating variants (frameshift, nonsense, splice, and start-loss variants)
  • Epilepsy is more common
• non-terminating variants (missense substitutions and in-frame duplications)

1.282. PTPRF, Protein Tyrosine Phosphatase Receptor Type F¶

Other names: LAR; Receptor-Type Tyrosine Protein Phosphatase F; Leukocyte Common Antigen-Related; EC 3.1.3.48; Protein Tyrosine Phosphatase, Receptor Type, F Polypeptide; Receptor-Linked Protein Tyrosine Phosphatase LAR; Leukocyte Antigen-Related Tyrosine Phosphatase; Leukocyte Antigen-Related (LAR) PTP Receptor; LCA Homolog; BNAH2

The PTPRF protein belongs to the protein tyrosine phosphatase (PTP) family. PTPs are e signaling molecules that regulate a wide range of cellular processes, including cell growth, differentiation, the mitotic cycle, and oncogenic transformation. PTPRF possesses an extracellular region, a single transmembrane region, and two tandem-like intracellular catalytic domains, making it a receptor-type PTP. The extracellular region contains three Ig-like domains and nine non-Ig-like domains that resemble those of the neural cell adhesion molecule. PTPRF plays a role in regulating epithelial cell contacts at adhesion sites as well as in controlling beta-catenin signaling. PTPRF may be a cell adhesion receptor. PTPRF possesses intrinsic protein tyrosine phosphatase (PTPase) activity and dephosphorylates EPHA2, thereby regulating its activity. The first PTPase domain has enzymatic activity, while the second domain appears to influence the substrate specificity of the first.²²²
PTPRF is associated with

• Aplasia/hypoplasia of the breasts/nipples, 2
• Isolated congenital breast hypoplasia / aplasia
• Insulin resistance
  • Increased PTPRF expression was observed in insulin-responsive tissue from obese, insulin-resistant individuals

Related signaling pathways:

• Unblocking of NMDA receptors
• Glutamate binding and activation
• Cadherin-mediated cell adhesion
• Binding of protein-containing complexes
• Phosphatase activity

Paralog: PTPRD

PTPRD is part of the same signaling pathway as CREB3, CSMD1, and GAB1, which are involved in neuronal differentiation and the dopamine pathway.¹⁵⁶

This gene was identified as a candidate for ADHD in a large-scale GWAS.¹⁹³

1.199. CSMD1, CUB, and Sushi Multiple Domains 1¶

Other names: KIAA1890; PPP1R24; Protein Phosphatase 1, Regulatory Subunit 24; CUB and Sushi Domain-Containing Protein 1; CUB and Sushi Multiple Domains Protein 1

The CSMD1 protein is thought to be involved in or upstream of several processes, such as

• Learning
• Memory
• Branching of the mammary glands during pregnancy
• Development of the reproductive organs
  CSMD1 is associated with
• Aceruloplasmia
• Schizophrenia

Paralog: CSMD2

UniProtKB/Swiss-Prot Summary for the CSMD1 Gene
Potential suppressor of squamous cell carcinomas. (CSMD1_HUMAN,Q96PZ7)

A study identified CSMD1 (variant rs6559123) as one of 96 ADHD candidate genes.¹⁵⁹

Norepinephrine¶

Norepinephrine synthesis¶

1.7. DBH, dopamine beta-hydroxylase (chromosome 9q34.2; Taql A)¶

The enzyme dopamine β-hydroxylase catalyzes the oxidation of dopamine to norepinephrine.

DBH is a candidate marker for ADHD.^{17164 1}
The C allele of the rs129882 SNP associated with ADHD reduced luciferase activity by half. Reduced DBH expression would be associated with decreased conversion of dopamine to norepinephrine and thus with a relative hypo-noradrenergic state in ADHD.²²³
In contrast, overexpression of DBH was not associated with elevated norepinephrine levels.²²⁴

DBH also appears to be a candidate for ASS.²²⁵

Effects of norepinephrine¶

1.46. ADRA1A, ALPHA-1A-ADRENERGIC RECEPTOR (Chromosome 8p21.2)¶

OMIM: ALPHA-1A-ADRENERGIC RECEPTOR; ADRA1A

In a 2006 study, the ADRA1A gene was identified as a candidate gene for ADHD with a p-value of 0.017.³

1.17. ADRA2A, ALPHA-2A-ADRENERGIC RECEPTOR (Chromosome 10q25.2)¶

OMIM: ALPHA-2A-ADRENERGIC RECEPTOR; ADRA2A

ADRA2A is a candidate gene for ADHD.¹¹⁶⁴⁹⁶

None of the ADRA2A polymorphisms (MspI and DraI) correlated significantly with the overall response to MPH. However, carriers of the G allele of the MspI polymorphism showed a correlation with a significant improvement in inattention symptoms.²²⁶
The alpha-2A-adrenergic receptor gene polymorphism modulates structural networks in the gray matter, visual memory, and inhibitory cognitive control in children with attention-deficit/hyperactivity disorder²²⁷

1.69. ADRA2C, ALPHA-2C-ADRENERGIC RECEPTOR (Chromosome 4p16.3)¶

OMIM: ALPHA-2C-ADRENERGIC RECEPTOR

Source¹⁶⁴

1.44. ADRB2, BETA-2-ADRENERGIC RECEPTOR (Chromosome 5q32)¶

OMIM: BETA-2-ADRENERGIC RECEPTOR; ADRB2

In a 2006 study, the ADRB2 gene was identified as a candidate gene for ADHD with a p-value of 0.013.³

Norepinephrine breakdown¶

Norepinephrine reuptake¶

1.18. NET, norepinephrine transporter gene (chromosome 16q12.2)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, NORADRENALINE), MEMBER 2; SLC6A2

The norepinephrine transporter reabsorbs more dopamine than norepinephrine in the PFC. See the section on dopamine reuptake above.

Of the four polymorphisms in the NET gene

• rs5569
• rs28386840
• rs2242446
• rs3785143
  carriers of the T allele of the rs28386840 polymorphism
• a significantly higher rate of response to MPH
• a significantly greater improvement in hyperactive-impulsive symptoms
  than the carriers of the other polymorphisms.
  ²²⁶

Development of the Norepinephrine System¶

1.329. MECP2¶

In the MeCP2 mutant mouse model of Rett syndrome, the HPA axis is overactivated, presumably due to increased expression of the CRH gene, which leads to abnormal stress responses. MeCP2 binds to the CRH promoter, which is normally enriched with methylated CpG dinucleotides.²²⁸ A MeCP2 deficiency impairs the noradrenergic system and causes respiratory distress. Administration of norepinephrine improved these symptoms.²²⁹

Reduced MECP2 expression was found in 11 of 14 people with ASD and in 2 of 2 people with ADHD.²³⁰ A case study also reports a link to ADHD.²³¹ SHR rats and rats exposed to PCBs showed alterations in the MECP2 gene.²³² Offspring of rat mothers that had been administered alcohol showed reduced MECP2 expression.²³³²³⁴ Alcohol consumption during pregnancy massively increases the risk of ADHD.

Serotonin¶

Serotonin synthesis¶

1.16. Tryptophan hydroxylase gene (chromosome 11p15.1)¶

Tryptophan hydroxylase is a candidate gene for ADHD.¹

1.77. TPH1, tryptophan hydroxylase-1 gene (chromosome 11p15.1)¶

OMIM: Tryptophan hydroxylase-1 gene; TPH1

A study found that the rare 218A-6526G haplotype of TPH1 was significantly less frequently passed on to offspring of individuals with ADHD.²³⁵

Another study found no association between the more common TPH1 or TPH2 haplotypes and ADHD-C.²³⁶

1.21. TPH2, tryptophan hydroxylase 2 gene (chromosome 12q21.1)¶

OMIM: Tryptophan hydroxylase 2 gene, TPH2

TPH2 is a candidate gene for ADHD.¹⁶⁴

The TPH2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.003.³ Another study was unable to confirm this finding for either TPH1 or TPH2.²³⁶

Stress-naive TPH2-/- mice (TPH2-KO mice) showed reduced dopamine levels in the hippocampus and PFC.²³⁷
In TPH2+/- mice, stress led to reduced dopamine levels:²³⁸

• In the hippocampus and striatum compared to stress-naive TPH2+/- mice.
• In the amygdala and PFC compared to stressed TPH2+/+ mice

The changes in the dopaminergic system of stressed TPH2+/- mice differed significantly from those in TPH2+/+ mice and closely resembled those in TPH2-/- mice.

Stressed TPH2-/- mice showed no particular changes in norepinephrine levels in the amygdala, PFC, hippocampus, dorsal raphe nuclei, or striatum. They merely exhibited (as did TPH2+/+ mice) the usual elevated norepinephrine levels in the PFC, hippocampus, and striatum compared to unstressed mice of the respective genotype.²³⁸

The TPH2 variant rs17110747 was associated with behavioral and cognitive symptoms of ADHD only in girls. A highly significant over-transmission of the G allele from parents to people with ADHD was observed. In addition, girls with the G/G genotype (rs17110747) responded better to placebo when assessed by their parents.²³⁹

Effects of Serotonin¶

1.13. HTR1B, Serotonin Receptor 1B (Chromosome 6q14.1)¶

Other names: 5-Hydroxytryptamine Receptor 1B

OMIM: 5-Hydroxytryptamine Receptor 1B

HTR-1B is a candidate gene for ADHD.¹⁶⁴¹

1.51. HTR1E, Serotonin Receptor 1E (Chromosome 6q14.3)¶

Other names: 5-HYDROXYTRYPTAMINE RECEPTOR 1E

OMIM: 5-Hydroxytryptamine Receptor 1E; HTR1E

The HTRE1E gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.051.³

1.14. HTR2A, serotonin receptor 2A (chromosome 13q14.2)¶

Other names: 5-Hydroxytryptamine Receptor 2A

OMIM: 5-Hydroxytryptamine Receptor 2A

HTR-2A is a candidate drug for ADHD.¹⁶⁴¹

Serotonin breakdown¶

Serotonin reuptake¶

1.15. SLC6A4, serotonin transporter gene, 5-HTT gene (chromosome 17q11.2)(x)¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, SEROTONIN), MEMBER 4; 5-HTTLPR long

OMIM: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, SEROTONIN), MEMBER 4; SLC6A4;

SLC6A4 is a candidate gene for ADHD.¹⁶⁴¹¹⁷

Serotonin Metabolism¶

1.20. Tryptophan 2,3-dioxynase (Chromosome 4q32.1)¶

The enzyme tryptophan-2,3-dioxygenase (TDO) oxidizes L-tryptophan by binding to two oxygen atoms. This is the first and rate-limiting step in the breakdown of tryptophan.

The tryptophan 2,3-dioxynase gene is a candidate gene for ADHD.²⁴⁰

Steroids¶

1.19. Androgen receptor (chromosome Xq11-q12)¶

The androgen receptor gene is a candidate gene for ADHD.²⁴⁰

GABA¶

1.162. SLC6A12, GABA transporter¶

Other names: Solute Carrier Family 6 Member 12; BGT-1; Solute Carrier Family 6 (Neurotransmitter Transporter, Betaine/GABA), Member 12; Solute Carrier Family 6 (Neurotransmitter Transporter), Member 12; Sodium- and Chloride-Dependent Betaine Transporter; Na(+)/Cl(-) Betaine/GABA Transporter; Betaine/GABA Transporter-1; Gamma-Aminobutyric Acid Transporter; BGT1; GAT2

SLC6A12 encodes a GABA transporter.
The SLC6A12 protein is involved in the transport of monocarboxylic acids. SLC6A12 is thought to be localized in the plasma membrane and is likely an integral component of the plasma membrane. SLC6A12 is thought to be active in neuronal projections. SLC6A12 transports betaine and GABA. It is likely to play a role in the regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation. Four 12-TM-domain transporters have been identified that are localized in neurons and glial cells.²⁴¹
SLC6A12 is associated with

• Spinocerebellar Ataxia 11
• Reflex epilepsy

SLC6A12 is a candidate gene for ADHD.²⁴²

1.319. SLC6A1, GABA transporter¶

Other names: Solute Carrier Family 6 Member 1, GABATR, GAT1, Sodium- and Chloride-Dependent GABA Transporter 1; GABATHG; Solute Carrier Family 6 (Neurotransmitter Transporter, GABA), Member 1; Solute Carrier Family 6 (Neurotransmitter Transporter), Member 1; GABA Transporter 1; HGAT-1; GAT-1; GABT1; MAE

SLC6A1 encodes the GABA-1 transporter.

SLC6A1 is a candidate gene for ADHD.²⁴³

1.22. GABA receptor alpha-3 (chromosome Xq28)¶

OMIM: GABA receptor alpha-3 gene

The GABA receptor A3 is a candidate gene for ADHD.¹

OMIM notes a role in relation to physical and psychological pain perception, as well as motor impairment and tolerance.

1.23. GABA receptor beta-3 (chromosome 15q11.2-q.12)¶

OMIM: GABA receptor beta-3 gene

The GABA receptor B3 is a candidate for ADHD.¹

OMIM notes that GABA receptors are zinc-regulated and that a polymorphism with particularly low sensitivity to zinc is known. OMIM does not mention ADHD, but it does mention autism, with which ADHD has a high rate of comorbidity.
There is speculation that ADHD and autism may share common neurological roots.²⁴⁴
Zinc deficiency can cause ADHD-like symptoms.

1.35. CDH13, Cadherin 13 (Chromosome 16q23.3)¶

Other names: CDHH; T-cadherin; H-cadherin (Heart); Heart cadherin; Cadherin-13; T-Cad; P105; Cadherin 13, H-Cadherin (Heart); runcated cadherin; H-Cadherin

Cadherin-13 influences GABAergic function in the hippocampus and cognition.²⁴⁵
The CDH13 protein is a member of the cadherin superfamily. CDH13 is localized to the cell membrane surface and is anchored by a GPI anchor rather than a transmembrane domain. CDH13 lacks the cytoplasmic domain characteristic of other cadherins, so it is not believed to be a cell-cell adhesion glycoprotein. CDH13 acts as a negative regulator of axon growth during neuronal differentiation. CDH13 also protects vascular endothelial cells from apoptosis induced by oxidative stress. Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner when cells join together; cadherins can therefore contribute to the sorting of heterogeneous cell types. They can act as negative regulators of neuronal cell growth.²⁴⁶
CDH13 is associated with

• Resistance to atherosclerosis
• many types of cancer (CDH13 is hypermethylated in these cancers)
• Vacterl Association
• Seminom

Paralog: CDH2

OMIM: Cadherin 13 (CDH13) gene

CDH 13 is a candidate gene for ADHD.²⁴⁷

• SNP rs7187223, position 81015234; intergenic, within 203 kb upstream of CDH13¹⁶⁴
  P: 5.21E−05.
• SNP s11646411, position 81304438; in the intron of CDH13¹⁶⁴
  P: 7.40E−06
• SNP rs6565113, position 81665146; intron of CDH13¹⁶⁴
• A study identified CDH13 (variant rs8055161) as one of the 20 most likely among 96 candidate genes¹⁵⁹

1.116. KIF21B, Kinesin Family Member 21B¶

Other names: KIAA0449, kinesin-like protein KIF21B, DKFZP434J212

The protein KIF21B is a member of the kinesin superfamily. Kinesins are ATP-dependent, microtubule-based motor proteins involved in the intracellular transport of membrane-bound organelles.

KIF21B is associated with

• inflammatory bowel diseases (single-nucleotide polymorphisms)
• Multiple sclerosis (single-nucleotide polymorphisms)

KIF21B is a plus-end-directed, microtubule-dependent motor protein with processive activity. KIF21B is involved in the regulation of microtubule dynamics, synaptic function, and neuronal morphology, including dendritic branching and spine formation. KIF21B plays a role in learning and memory. KIF21B is involved in the transport of the gamma-aminobutyric acid (GABA(A)) receptor to the cell surface.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

Acetylcholine¶

Acetylcholine action¶

1.32. CHRNA7, Alpha-7 neuronal nicotinic acetylcholine receptor¶

The protein “Neuronal Acetylcholine Receptor Subunit Alpha-7” (nAChRα7) is a subunit of certain nicotinic acetylcholine receptors (nAchR).

OMIM: Alpha-7 neuronal nicotinic acetylcholine receptor (CHRNA7) gene

CHRNA 7 is a candidate gene for ADHD.²⁴⁸

1.50. CHRNA4, Alpha-4 neuronal nicotinic acetylcholine receptor (chromosome 20q13.33)¶

Other names: CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4

OMIM: CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4

The CHRNA4 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.05.³¹⁶⁴ A review also describes a link between CHRNA4 and ADHD.²⁴⁹

1.212. LYPD1, LY6/PLAUR Domain-Containing 1¶

Other names: LYPDC1; Ly6/PLAUR Domain-Containing Protein 1; Putative HeLa Tumor Suppressor; MGC29643; PHTS

The LYPD1 protein is thought to act as a modulator of nicotinic acetylcholine receptor (nAChR) activity and exhibits both acetylcholine receptor-binding activity and acetylcholine receptor-inhibitory activity.In vitro, LYPD1 increases receptor desensitization and reduces the affinity for ACh of alpha-4:beta-2-containing nAChRs. LYPD1 may play a role in the intracellular transport of alpha-4:beta-2- and alpha-7-containing nAChRs and inhibits their expression on the cell surface. LYPD1 is involved in posttranslational modification: synthesis of GPI-anchored proteins and protein metabolism. LYPD1 may be involved in the regulation of anxiety.²⁵⁰
LYPD1 is associated with

• Distal arthrogryposis, type 2A
• melanotic medulloblastoma

Paralog: LYPD2

A study identified LYPD1 (variant rs7561232) as one of 96 ADHD candidate genes.¹⁵⁹

Choline¶

Choline breakdown¶

1.40. SLC5A7, CHT1, CHOLINE TRANSPORTER¶

Other names: SOLUTE CARRIER FAMILY 5 (), MEMBER 7; CHT1; Solute Carrier Family 5 (Sodium/Choline Cotransporter), Member 7; High-Affinity Choline Transporter 1; HCHT; High-Affinity Choline Transporter; Hemicholinium-3-Sensitive Choline Transporter; Solute Carrier Family 5 (Choline Transporter), Member 7; Hemicholinium-3-Sensitive Choline Transporter; CMS20; HMN7A

OMIM: CHT, SOLUTE CARRIER FAMILY 5 (CHOLINE TRANSPORTER), MEMBER 7; SLC5A7

The SLC5A7 protein is a sodium- and chloride-ion-dependent high-affinity transporter that mediates the uptake of choline for acetylcholine synthesis in cholinergic neurons. SLC5A7 transports choline from the extracellular space into presynaptic terminals for the synthesis of acetylcholine. Increased choline uptake results from an increased density of this protein in synaptosomal plasma membranes in response to the depolarization of cholinergic terminals. SLC5A7 is a transmembrane transporter that imports choline from the extracellular space into the neuron with high affinity. Choline uptake is the rate-limiting step in acetylcholine synthesis. SLC5A7 is sodium- and chloride-dependent.²⁵¹
SLC5A7 is associated with

• Myasthenic syndrome, congenital, 20, presynaptic
• Distal hereditary motor neuropathy, Type VIIA (autosomal dominant distal hereditary motor neuropathy, Type VIIA)
• Depression
• ADHD
• Schizophrenia

Paralog: SLC5A2

SLC5A7 – the coding variant Ile89Val (rs1013940) is two to three times more common in people with ADHD (n = 100; P = 0.02) and is reported to correlate with ADHD-C (OR = 3.16; P = 0.01), whereas the coding variant SNP 3’ (rs333229) occurs significantly less frequently in people with ADHD than in people without ADHD (n = 60; P = 0.004).²⁵²

1.237. SLC44A1, Solute Carrier Family 44, Member 1¶

Other names: CTL1; CD92; CHTL1; CDW92; Solute Carrier Family 44 (Choline Transporter), Member 1; Choline Transporter-Like Protein 1; CDW92 Antigen; CDw92; CD92 Antigen; CONATOC

The SLC44A1 protein is a choline transmembrane transporter. SLC44A1 is involved in choline transport and transmembrane transport. SLC44A1 is found in several cellular components, including the cytosol, the mitochondria, and the nucleoplasm. SLC44A1 is associated with high-grade gliomas. SLC44A1 is involved in membrane synthesis and myelin production.²⁵³
SLC44A1 is associated with

• Neurodegeneration, beginning in childhood
• Ataxia
• Tremor
• Optic atrophy
• cognitive decline
• postural orthostatic tachycardia syndrome

Paralog: SLC44A3

A study identified SLC44A1 (variant rs10991581) as one of 96 ADHD candidate genes.¹⁵⁹

Glutamate¶

1.39. GRM1, Metabotropic Glutamate Receptor 1 (Chromosome 6p24-3)¶

OMIM:Metabotropic glutamate receptor 1 (GRM1) gene

GRM1 is a candidate gene for ADHD.²⁵⁴

1.225. GRIK3, Glutamate Ionotropic Receptor Kainate Type Subunit 3¶

Other names: GluK3; GLUR7; Ionotropic Glutamate Receptor, Kainate 3; Excitatory Amino Acid Receptor 5; Glutamate Receptor 7; GluR-7; EAA5; DJ1090M5.1 (Glutamate Receptor, Ionotropic, Kainate 3 (GLUR7)); Glutamate Receptor, Ionotropic, Kainate 3; GluR7a; GluR7; GLR7

GRIK3 is a glutamate receptor. Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated during a wide range of normal neurophysiological processes. GRIK3 belongs to the kainate family of glutamate receptors, which consist of four subunits and function as ligand-activated ion channels. It is unclear whether the subunit encoded by this gene undergoes RNA editing, as do the other two family members (GRIK1 and GRIK2). Kainate receptors have been identified in both presynaptic and postsynaptic locations. The glutamate receptor GRIK2 binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.²⁵⁵
GRIK3 is associated with:

• Schizophrenia (a Ser310Ala polymorphism)
• There are conflicting reports regarding its role in the pathogenesis of delirium tremens in alcoholics
• Depersonalization Disorder

Paralog: GRIK2

A study identified GRIK3 (variant rs1032722) as one of 96 ADHD candidate genes.¹⁵⁹

1.312. GRIK1, Glutamate Ionotropic Receptor Kainate Type Subunit 1¶

A study examined the GRIK1 variants rs363504 and rs363538 by measuring GRIK1 expression in peripheral blood.²⁵⁶

• The participants and their fathers had a higher frequency of the rs363504 ‘CC’ and rs363538 ‘CA’ genotypes.
• Rs363504 ‘C’ and rs363538 ‘A’ were inherited by the subjects from their mother.
• Rs363504 ‘TT’ and rs363538 ‘AA’ were associated with higher hyperactivity scores.
• Rs363504 ‘TT’ and rs363538 ‘CC’ were associated with improvements in hyperactivity and inattention, respectively, following treatment with MPH.
• GRIK1 expression was significantly downregulated in the study participants.

1.34. GRM5, Metabotropic glutamate receptor 5 (Chromosome 11q14..2 – 14.3) (33, p. 55)¶

OMIM: Metabotropic glutamate receptor 5 (GRM5) gene

GRM5 is a candidate gene for ADHD.²⁵⁴¹ A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.38. GRM7, Metabotropic glutamate receptor 7 (Chromosome 3p26.1)¶

OMIM: Metabotropic glutamate receptor 7 (GRM7) gene

GRM7 is a candidate gene for ADHD.²⁵⁴²⁵⁷

The GMR7 rs3792452 polymorphism influences the response to methylphenidate in children with ADHD.²⁵⁸

1.43. SLC9A9, Solute Carrier Family 9 Member A9 (Chromosome 3q24)¶

Other names: NHE9; Solute Carrier Family 9, Subfamily A (NHE9, Cation-Proton Antiporter 9), Member 9; Sodium/Hydrogen Exchanger 9; Na(+)/H(+) Exchanger 9; FLJ35613; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger), Isoform 9; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger), Member 9; Solute Carrier Family 9 (Sodium/Hydrogen Exchanger); Putative Protein Product of Nbla00118; Solute Carrier Family 9 Member 9; Sodium/Proton Exchanger NHE9; AUTS16; NHE-9

The SLC9A9 gene encodes a sodium/proton exchanger belonging to the Solute Carrier 9 (SLC9) family of proteins. SLC9A9 is localized in late recycling endosomes and appears to play a role in maintaining cation homeostasis. SLC9A9 is involved in

• electroneutral exchange of protons for Na(+) across membranes
• Excretion of luminal H(+) from the Golgi apparatus in exchange for cytosolic cations
• Ion homeostasis of organelles by helping to maintain the unique acidic pH levels of the Golgi and post-Golgi compartments within the cell.²⁵⁹
  The SLC9A9 protein counteracts endosomal acidification by alkalizing the system. SLC9A9 controls the strict pH regulation of the endosomal system and clathrin-mediated endocytosis.²⁶⁰ SLC9A9 consequently regulates pan-receptor recycling.
  Increased SLC9A9 expression in mouse astrocytes²⁶⁰
• increased the surface localization and recycling of the glutamate transporter **(GLAST) **
• increased intake of glutamate
  Elevated SLC9A9 Expression in Glioblastoma Multiforme (GBM) Cell Lines²⁶⁰
• increased the surface localization of the endothelial growth factor receptor (EGFR)
• increased tumor invasiveness
  Increased SLC9A9 expression²⁶⁰
• increased the internalization and recycling of transferrin receptors in HEK293 cells, microvascular endothelial cells of the brain, and glioma cells
  By regulating transferrin receptor recycling, SLC9A9 plays an important role in iron metabolism.
  **Iron deficiency causes **²⁶⁰
• Increased SLC9A9 expression in human brain microvascular endothelial cells (hBMVECs), which form the blood-brain barrier (BBB)
• increased iron uptake by the ** ** across the blood-brain barrier by
  • Upregulation of transferrin receptor expression
  • Increase in endosomal pH
  • increased translocation of TfRs to the hBMVEC membrane
    Amino acid deficiency causes²⁶⁰
• Increased SLC9A9 expression in immortalized hypothalamic neurons and primary cortical cells
  SLC9A9 regulates cellular nutrients and cell metabolism.²⁶⁰.
  SLC9A9 is associated with:
• ADHD²⁶¹²⁶²
• Autism 16²⁶¹
  • An ASD nonsense mutation in SLC9A9, R423X, did not produce any detectable amount of SLC9A9, suggesting a complete loss of SLC9A9 functional networks in ASD. Furthermore, seven of the SLC9A9 interactors are products of known autism candidate genes, and 90% of the SLC9A9 interactome overlaps with the SFARI protein interaction network (PIN) (p < 0.0001), which supports the role of the SLC9A9 interactome in the molecular mechanisms of ASD.
• Colon cancer

Related metabolic pathways:

• Transport of inorganic cations/anions and amino acids/oligopeptides
• Solute:Proton Antiporter Activity
• Sodium:Proton Antiporter Activity

Paralog: SLC9A7

OMIM: SOLUTE CARRIER FAMILY 9 (SODIUM/HYDROGEN EXCHANGER), MEMBER 9; SLC9A9

A study identified 100 proteins that interact with SLC9A9. These proteins were enriched in known functional pathways for SLC9A9:²⁶²

• Endocytosis
• Protein ubiquitination
• Phagosome pathways
• oxidative stress
• mitochondrial dysfunction
• mTOR signaling
• Cell death
• RNA processing pathways

The A409P mutation associated with ADHD significantly altered the interactions of SLC9A9 with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling.²⁶²
The SLC9A9 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.01.³ Another study identified SLC9A9 (variant rs7621206) as one of the 20 most likely among 96 candidate genes.¹⁵⁹ A further study also identified SLC9A9 as the gene with the strongest correlation among the genes examined.²⁰,

Cannabinoids¶

1.37. CNR1, Cannabinoid Receptor 1 (Chromosome 6q14-q15) (x)¶

Other names: CANN6; CB-R; CB1; CB1K5; CB1A; CNR; Cannabinoid Receptor 1 (Brain); Central Cannabinoid Receptor; CB1R²⁶³
OMIM: Cannabinoid Receptor 1 (CNR1) gene

CNR1 acts on the cannabinoid 1 receptor (CB1). This receptor inhibits motor function and impulsivity, which are mediated by the dopaminergic system.
In SHR with impulsivity, CB1 was reduced.
A gene-environment interaction has been reported for the CNR1 gene variants rs806379 and rs1049353 in relation to early childhood trauma, which increases the risk of impulsivity but not of novelty seeking.²⁶⁴
Four SNPs in or near the CNR1 gene were significantly correlated with impulsivity:²⁶⁵

• rs1535255 (p = .001)
• rs2023239 (p = .004)
• rs1049353 (p < .001)
• rs806368 (p < .0006).

CNR1 is a candidate gene for ADHD.^266267247
The SNP haplotype (C-G) was strongly correlated with ADHD (P = 0.008).²⁶⁸

In addition, CNR1 is associated with:²⁶⁹

• Addiction
• Obesity
• Depression
• Anxiety
• PTSD
• Schizophrenia
• striatal response to faces

The CBR1 gene variant CB1F238L exhibits a mutation from phenylalanine 238 to leucine. At the cellular level, CB1F238L causes a significant reduction in presynaptic neurotransmitter release and, in rats, leads to increased risk-taking behavior, increased social play behavior, and increased reward sensitivity.²⁷⁰

1.401. FAAH (x)¶

FAAH is responsible for the breakdown of cannabinoids such as anandamide (AEA).
ADHD is associated with elevated AEA levels.

FAAH rs2295633 is a candidate gene for ADHD.²⁷¹ A significant difference was found in the allele frequency (P = .04) and genotype distribution (P = .04) of FAAH rs2295633 between ADHD cases and controls. The TT genotype (OR 0.396) and the T allele (OR 0.658) were less common in ADHD.

The C385A allele of the rs324420polymorphism of the FAAH gene was associated with elevated AEA levels, improved fear extinction, and reduced amygdala reactivity during recall of fear extinction.²⁷²²⁷³

Trace amines¶

1.42. PNMT, Phenylethanolamine N-Methyltransferase (Chromosome 17q12)¶

OMIM: Phenylethanolamine N-methyltransferase gene, PNMT

The PNMT gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.008.³

Glycine¶

1.89. SLC6A9, Glycine Transporter¶

Other names: SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 9

OMIM: SLC6A9, SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 9

Several studies have found altered expression of SLC6A9 in ADHD.¹¹⁷¹⁴⁸

Nitric oxide¶

1.36. NOS1, Nitric Oxide Synthase 1 (Chromosome 12q24.22) (87)¶

The protein nitric oxide synthase 1 belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a biological mediator of, among other things, neurotransmission, antimicrobial, and antitumor activities. In the brain and the peripheral nervous system, nitric oxide exhibits many of the properties of a neurotransmitter. It is involved in

• Neurotoxicity in relation to strokes
• neurodegenerative diseases
• neural regulation of smooth muscle, including peristalsis and penile erection.

OMIM: Nitric Oxide Synthase 1 (NOS1) Gene

Nitric oxide (NO) is involved in schizophrenia, ADHD, and possibly mood disorders:²⁷⁴

Genetically determined reduced NO signaling in the PFC has been linked to schizophrenia and cognitive problems. Both NOS1 and its interaction partner, NOS1AP, play a role in this process.
Reduced NOS1 expression in the striatum due to a length polymorphism in the NOS1 promoter (NOS1 ex1f-VNTR) correlates with impulsivity.
NOS1 may be associated with mood disorders. NO metabolites in the blood may serve as biomarkers for major depression and bipolar disorders. .

NOS 1 (short allele) is a candidate gene for increased impulsivity and, consequently, for ADHD.²⁴⁷²⁷⁵
NOS1-KO models are used to simulate ADHD.²⁷⁶

Neurotransmitter Storage and Release¶

1.114. CPLX2, Complexin 2¶

Other names: CPX-2, DKFZp547D155, Complexin II, Complexin-2

CPLX2 is a cytosolic protein that plays a role in the exocytosis of synaptic vesicles. It binds to syntaxin, a component of the SNAP receptor, and disrupts it, thereby enabling the release of neurotransmitters. CPLX2 inhibits the formation of synaptic vesicle clusters at the active zone on the presynaptic membrane in postmitotic neurons. CPLX2 promotes a late step in the exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. CPLX2 is involved in the exocytosis of mast cells.²⁷⁷

CPLX2 is associated with

• Schizophrenia
• Epilepsy, familial temporal lobe, 7.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.177. STXBP6, Syntaxin-Binding Protein 6¶

Other names: Amisyn; HSPC156; Syntaxin-Binding Protein 6

STXBP6 forms non-fusogenic complexes with SNAP25 and STX1A and can thereby modulate the formation of functional SNARE complexes and exocytosis.²⁷⁸
STXBP6 is associated with:

• Deafness, autosomal dominant 23
• Deafness, autosomal recessive 35

Paralog: EXOC1

A study identified STXBP6 (variant rs17200947) as one of 96 ADHD candidate genes.¹⁵⁹

1.242. MYO5B, Myosin VB¶

Other names: KIAA1119; Unconventional Myosin-Vb; MYO5B Variant Protein; Myosin-Vb; PFIC10; DIAR2; MVID1

The MYO5B protein may be involved in plasma membrane recycling in conjunction with other proteins. MYO5B may be involved in vesicular trafficking through its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling, but not for EGFR degradation. MYO5B is required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. MYO5B, together with RAB11A, is involved in CFTR transport to the plasma membrane and in TF (transferrin) recycling in nonpolarized cells. MYO5B, together with RAB11A and RAB8A, is involved in the polarization of epithelial cells. MYO5B, together with RAB25, regulates transcytosis.²⁷⁹
MYO5B is associated with

• Diarrhea 2
• Microvillus atrophy, with or without cholestasis
• Microvillus Inclusion Disease

Paralog: MYO5A

A study identified MYO5B (variant rs1787319) as one of 96 ADHD candidate genes.¹⁵⁹

1.263. TRAPPC11, Trafficking Protein Particle Complex Subunit 11¶

Other names: C4orf41; Trafficking Protein Particle Complex 11; FLJ12716; Foigr; Gry; Chromosome 4 Open Reading Frame 41; Foie Gras Homolog (Zebrafish); Gryzun Homolog (Drosophila); Foie Gras Homolog; Gryzun Homolog; LGMDR18; LGMD2S; FOIGR; GRY

The TRAPPC11 protein is a subunit of the TRAPP (transport protein particle) tethering complex, which is responsible for intracellular vesicle transport. TRAPPC11 is involved in the early phase of vesicle transport from the endoplasmic reticulum to the Golgi apparatus.²⁸⁰
TRAPPC11 is associated with

• Muscular dystrophy
• Limb girdle dystrophy, autosomal recessive 18
• Intellectual Disability-Hyperkinetic Movement-Trunk Ataxia Syndrome

Related metabolic pathways:

• Vesicle-mediated transport
• Rab Regulation on Trafficking.

UniProtKB/Swiss-Prot Summary for the TRAPPC11 Gene
Is involved in the transport from the endoplasmic reticulum to the Golgi apparatus at a very early stage. (TPC11_HUMAN,Q7Z392)

A study identified TRAPPC11 (variant rs10018951) as one of 96 ADHD candidate genes.¹⁵⁹

Fatty acids¶

1.48. FADS2, FATTY ACID DESATURASE 2 (Chromosome 11q12.2)¶

Other names: D6D; SLL0262; FADSD6; TU13; DES6; Acyl-CoA 6-Desaturase; Delta-6-Desaturase; LLCDL2; Linoleoyl-CoA Desaturase (Delta-6-Desaturase)-Like 2; Delta(6) Fatty Acid Desaturase; Delta-6 Fatty Acid Desaturase; Delta(6) Desaturase; Delta-6 Desaturase; EC 1.14.19.3; EC 1.14.19

The enzyme FADS2 removes two hydrogen atoms from a fatty acid, creating a carbon-carbon double bond.
FADS2 belongs to the family of fatty acid desaturase (FADS) genes. Desaturase enzymes regulate the unsaturation of fatty acids by introducing double bonds between specific carbon atoms in the fatty acyl chain. Members of the FADS family are considered fusion proteins consisting of an N-terminal cytochrome b5-like domain and a C-terminal transmembrane desaturase domain, both of which are characterized by conserved histidine motifs. This gene is clustered with family members at 11q12-q13.1; due to the similar exon/intron organization, it is believed that this cluster arose evolutionarily through gene duplication. FADS2 is involved in the biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3), which act as fatty acid acyl-coenzyme A (CoA) desaturases that introduce a cis double bond at carbon 6 of the fatty acyl chain. FADS2 catalyzes the first and rate-limiting step in this metabolic pathway, namely the desaturation of LA (18:2n-6) and ALA (18:3n-3) to gamma-linolenic (GLA) (18:3n-6) and stearidonic acid (18:4n-3), respectively (PubMed:12713571). Subsequently, in the biosynthetic pathway of the n-3 HUFA series, FADS2 desaturates tetracosapentaenoate (24:5n-3) to tetracosahexaenoate (24:6n-3), which is then converted to docosahexaenoate (DHA) (22:6n-3), an important lipid for nervous system function. FADS2 desaturates hexadecanoate (palmitate) to produce 6Z-hexadecenoate (sapienate), a fatty acid found only in humans and a major component of human sebum. It is associated with the development of acne and may have a strong antibacterial effect. FADS2 can desaturate (11E)-octadecenoate (trans-vaccenoate, the predominant trans fatty acid in human milk) at carbon 6, producing (6Z,11E)-octadecadienoate. In addition to its delta-6 activity, FADS2 exhibits delta-8 activity with a slight preference for n-3 fatty acyl-CoA substrates.²⁸¹
FADS2 is associated with:

• Fetal Akinesia Deformation Sequence 4
• Hyperlipoproteinemia, Type V

FADS2 plays a role in the biosynthesis of polyunsaturated fatty acids (PUFAs).

Related metabolic and signaling pathways:

• Alpha-linolenic acid (ALA)
• Arachidonic acid biosynthesis III (6-desaturase, mammals)
• Iron ion binding
• Oxidoreductase activity that acts on paired donors, whereby the oxidation of a donor pair leads to the reduction of molecular oxygen to two water molecules

Paralog: FADS3

OMIM: Fatty Acid Desaturase 2; FADS2

The FADS2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.039.³

In a study of sphingolipid metabolism genes, the FADS3 gene was identified as a possible candidate gene for ADHD in one of three subject cohorts. This finding could not be replicated in the other two cohorts.²⁸²

1.366. GALC¶

rs74073730 in GALC was identified as a potential candidate gene for ADHD in a study of sphingolipid metabolism genes across three subject cohorts.²⁸²
rs398607 was associated with increased GALC expression in the cerebellum.

Sphingolipids are essential for myelination and the growth and maturation of neurites.

1.367. SMPD1¶

rs35785620 in SMPD1 was identified as a potential candidate gene for ADHD in a study of sphingolipid metabolism genes conducted across three pools of participants.²⁸²

1.368. CERS6¶

rs4668077 in CERS6 was identified as a potential candidate gene for ADHD in a study of sphingolipid metabolism genes conducted across three pools of participants.²⁸²

CERS6KO mice, which lack CERS6, exhibit hyperactivity.²⁸³

1.369. CERS2¶

rs139609178 in CERS2 was identified as a potential candidate gene for ADHD in a study of sphingolipid metabolism genes across three pools of participants.²⁸²

Brain Development¶

1.33. NDE1, Nuclear Distribution Gene E Homolog 1¶

Other names: NudE Neurodevelopment Protein 1; NudE; NDE; Nuclear Distribution Protein NudE Homolog 1; FLJ20101; NUDE; NudE Nuclear Distribution Gene E Homolog 1 (A. nidulans); NudE Nuclear Distribution E Homolog 1 (A. nidulans); LIS1-Interacting Protein NUDE1, Rat Homolog; Epididymal Secretory Sperm-Binding Protein; NudE Nuclear Distribution Gene E Homolog 1; NudE Nuclear Distribution E Homolog 1; HOM-TES-87; NUDE1; LIS4; MHAC

NDE1 is a member of the Nuclear Distribution E (NudE) protein family, is localized to the centrosome, and is required for:²⁸⁴

• Development of the cortex
• Centrosome duplication
• Formation and Function of the Mitotic Spindle
• Organization of microtubules
• Mitosis
• neuronal migration
• Regulation of dynein function

NDE1 is associated with

• Microhydranencephaly
• Lissencephaly 4
  • characterized by: lissencephaly, severe cerebral atrophy, microcephaly, severe cognitive impairments

Related signaling pathways:

• Cell cycle
• Mitosis
• EML4
• NUDC in mitotic spindle formation
• identical protein binding
• Microtubule binding

Paralog: NDEL1

OMIM: Nuclear distribution gene E homologue 1 (NDE1) gene

NDE1 is a candidate gene for ADHD.²⁴⁸

1.106. MAP1B, Microtubule-Associated Protein 1B¶

Other names: PPP1R102, MAP5, Protein Phosphatase 1, Regulatory Subunit 102

The MAP1B protein belongs to the family of microtubule-associated proteins, which are thought to be involved in microtubule assembly—a crucial step in neurogenesis. MAP1B is a precursor polypeptide that is thought to form, following proteolytic processing, the final heavy chain of MAP1B and the light chain of LC1. Studies in MAP1B knockout mice suggest an important role in the development and function of the nervous system. MAP1B facilitates the tyrosination of alpha-tubulin in neuronal microtubules. Phosphorylated MAP1B appears to play a role in the cytoskeletal changes associated with neurite outgrowth. MAP1B acts as a positive cofactor in DAPK1-mediated autophagic vesicle formation and membrane blebbing.²⁸⁵
MAP1B is associated with

• Periventricular Nodular Heterotopia 9
• Deafness, Autosomal Dominant 83

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.107. MOBP, Myelin-Associated Oligodendrocyte Basic Protein¶

The MOBP protein is thought to facilitate actin- and myosin-binding activity. MOBP appears to be a structural component of the myelin sheath (possibly by binding to the negatively charged acidic phospholipids of the cytoplasmic membrane) and to be involved in the development of the nervous system. It is likely found in the mitochondria and is active in the cortical actin cytoskeleton.

MOBP is associated with frontotemporal dementia and cocaine abuse

A study identified this gene as one of the 51 most likely candidate genes for ADHD.²⁸⁶

1.56. ASTN2, ASTROTACTIN 2 (Chromosome 9q33.1)¶

The proteins astrotactin-1 and 2 (ASTN-1 and ASTN-2) are integral membrane-bound perforin-like proteins. They play a crucial role in neurodevelopment. Genetic variations in these proteins have been linked to a range of neurodevelopmental disorders and other neurological pathologies, including early-onset Alzheimer’s disease. ASTN-2 (unlike ASTN-1) binds inositol triphosphate, suggesting a mechanism for membrane recognition or for the regulation of its activity by secondary messengers.

Astrotactin 2 (ASTN2) regulates neuronal migration and synaptic strength by transporting and degrading surface proteins.
ASTN2 deletions in copy number variants have been identified in:²⁸⁷

• Schizophrenia
• bipolar disorder
• ASS

whether a deficiency in ASTN2 affects cognitive and/or emotional behaviors and neurotransmission, using ASTN2-deficient mice.
Astn2 knockout mice showed:²⁸⁷

• no apparent differences in physical characteristics or circadian rhythms
• increased exploratory behavior in a new environment
• increased social behavior
• increased impulsivity
• reduced despair and anxiety-like behaviors
• reduced preference for exploring new objects
• reduced dopamine levels in the striatum
• increased dopamine and serotonin turnover in the striatum, nucleus accumbens, and amygdala
• Thinning of the neural cell layers in the hippocampus
• Reduction in the number of neuronal cell bodies in the PFC
• Decrease in spine density and PSD95 protein levels in the hippocampus and PFC

OMIM: ASTROTACTIN 2; ASTN2

• SMP: rs10983238 Position: 118373504; In the intron of ASTN2¹⁶⁴
  p: 1.37E−07
  A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.110. TCF4, Transcription Factor 4¶

Other names: BHLHb19, ITF2, Class B Basic Helix-Loop-Helix Protein 19, Immunoglobulin Transcription Factor 2, SL3-3 Enhancer Factor 2, SEF2-1B, E2-2, ITF-2

The TCF4 protein is a basic helix-loop-helix transcription factor. It recognizes an Ephrussi box (“E-box”) binding site (“CANNTG”). TCF4 is widely expressed and may play an important role in the development of the nervous system. TCF4 is involved in the initiation of neuronal differentiation. TCF4 binds to the immunoglobulin enhancer Mu-E5/KE5 motif. TCF4 binds to the E-box in the somatostatin receptor 2 initiator element (SSTR2-INR) and the E-box (5’-CANNTG-3’) to activate transcription.

TCF4 is associated with

• Pitt-Hopkins syndrome
• Fuchs’ endothelial corneal dystrophy

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.111. TLL2, Tolloid-Like 2¶

Other names: Tolloid-like protein 2, EC 3.4.24.19, EC 3.4.24, EC 3.4.24, KIAA0932

The TLL2 protein is an astacin-like zinc-dependent metalloprotease and a member of the Metzincin subfamily. TLL2 is a predominant protease and specifically processes pro-lysyl oxidase. TLL2 is essential for embryonic development and influences the development of the dorsal-ventral patterning and skeletal formation.

TLL2 is associated with

• Powassan encephalitis
• Louping, Illinois

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.117. TENM4, Teneurin Transmembrane Protein 4¶

Other names: Ten-M4, KIAA1302, TEN4, ODZ4, Odd Oz/Ten-M homolog 4, Tenascin-M4

The TENM4 protein plays a role in establishing proper neuronal connectivity during development. TENM4 is involved in the formation of the anterior-posterior axis during gastrulation. TENM4 regulates the differentiation and cellular process formation of oligodendrocytes and the myelination of small-diameter axons in the central nervous system (CNS). TENM4 promotes the activation of focal adhesion kinase. TENM4 can act as a cellular signaling molecule.

TENM4 is associated with tremor.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.91. ANK3, ANKYRIN 3¶

Since a study of 27 people with ADHD and dysfunctional ANK3 gene variants found that 57% had ADHD, we have listed ANK3 under monogenic causes of ADHD .

1.120. ANKS1B, Ankyrin Repeat and Sterile Alpha Motif Domain-Containing 1B¶

Other names: AIDA-1, EB-1, Cajalin-2, ANKS2, Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B

ANKS1B is a multidomain protein found primarily in the brain and testes. ANKS1B interacts with the amyloid-beta protein precursor (AbetaPP) and may play a role in normal brain development and in the pathogenesis of Alzheimer’s disease. Isoform 2 may be involved in regulating nucleoplasmic coilin-protein interactions in neuronal and transformed cells. Isoform 3 may regulate global protein synthesis by altering the number of nucleoli. Isoform 4 may play a role as a modulator of APP processing. Overexpression may downregulate APP processing.²⁸⁸

ANKS1B is associated with

• Alzheimer’s
• Acute lymphoblastic pre-B-cell leukemia

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.233. EPHA7, EPH Receptor A7¶

Other names: HEK11; Ephrin Type-A Receptor 7; EPH Homology Kinase 3; EPH-Like Kinase 11; EC 2.7.10.1; Hek11; EHK-3; EHK3; EK11; Receptor Protein Tyrosine Kinase HEK11; Tyrosine Protein Kinase Receptor EHK-3; Eph Homology Kinase-3; EC 2.7.10; EphA7

The EPHA7 protein belongs to the ephrin receptor subfamily of the protein tyrosine kinase family. EPH and EPH-related receptors are involved in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region that contains a cysteine-rich domain and two fibronectin type III repeats. Ephrin receptors are classified into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. EPHA7 is a receptor tyrosine kinase that promiscuously binds GPI-anchored ligands of the Ephrin-A family located on neighboring cells, leading to contact-dependent bidirectional signal transduction to neighboring cells.
The signaling pathway downstream of the receptor is referred to as forward signaling, while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among the GPI-anchored Ephrin-A ligands, EFNA5 is a cognate/functional ligand for EPHA7, and their interaction regulates brain development by modulating cell-cell adhesion and repulsion. EFNA5 has a repulsive effect on axons and is involved, for example, in the guidance of corticothalamic axons and in the correct topographic mapping of retinal axons to the colliculus. EPHA7 can also regulate brain development through caspase (CASP3)-dependent proapoptotic activity. Forward signaling can lead to the activation of components of the ERK signaling pathway, including MAP2K1, MAP2K2, MAPK1, and MAPK3, which are phosphorylated upon activation of EPHA7.²⁸⁹
EPHA7 is associated with

• Brachydactyly-syndactyly syndrome
• Brachydactyly, Type A4
• various types of cancer associated with increased gene expression

Paralog: EPHA5

A study identified EPHA7 (variant rs16870710) as one of 96 ADHD candidate genes.¹⁵⁹

1.299. SEMA6D, Semaphorin 6D¶

Other names: KIAA1479; Sema Domain, Transmembrane Domain (TM), and Cytoplasmic Domain, (Semaphorin) 6D; Semaphorin-6D; FLJ11598

SEMA6D is a class 6 transmembrane semaphorin in vertebrates. Semaphorins are a large family that includes both secreted and membrane-associated proteins, many of which act as inhibitors or chemorepellents in axon guidance, fasciculation, and branching, as well as in target selection. All semaphorins possess a semaphorin domain (Sema) and a PSI domain (found in plexins, semaphorins, and integrins) in the N-terminal extracellular region. Additional sequence motifs at the C-terminus of the semaphorin domain allow for classification into different subfamilies. Transmembrane semaphorins, like secreted semaphorins, can act as repulsive axon guidance markers. SEMA6D acted in vitro on dorsal root ganglion (DRG) neurons. SEMA6D may act as a stop signal for DRG neurons in their target regions and possibly for other neurons as well. SEMA6D may also be involved in the maintenance and remodeling of neuronal connections.²⁹⁰
SEMA6D is associated with

• Cone-rod dystrophy 10
• Kallmann syndrome

Related signal paths:

• Semaphorin interactions
• Development of the nervous system
• Signal receptor activity
• Semaphorin-receptor binding

Paralog: SEMA6A

This gene was identified as a candidate for ADHD in a large-scale GWAS.¹⁹³
SEMA6D has been identified as a candidate gene for ADHD.²⁹¹.

1.63. NAV2, NEURON NAVIGATOR 2 (Chromosome 11p15.1)¶

Other names: APC down-regulated 1; FLJ10633; FLJ11030; FLJ23707; HELAD1; KIAA1419; POMFIL2; RAINB1, helicase, pore membrane and/or filament-interacting-like protein 2; Retinoic acid-inducible gene in neuroblastoma 1;

The Neuron Navigator 2 (NAV2) protein is a member of the Neuron Navigator protein family. NAV2 is widely distributed in the central nervous system (CNS), particularly in the developing cerebellum. NAV2 is critical for cytoskeletal dynamics and neurite growth.²⁹²
Nav2 is associated with

• Cerebellar hypoplasia with abnormal folding due to impaired axonal outgrowth
• Corpus callosum hypodysgenesis
• Agenesis of the olfactory bulbs
• defects in cell migration
• NAV2 anomalies are usually fatal.²⁹²

OMIM: NEURON NAVIGATOR 2

The SNP rs874426, located at position 19526139 in the intron of NAV2, was identified as a candidate gene for ADHD with a p-value of 3.75E−06.¹⁶⁴

1.119. CNNM2, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 2¶

Other names: ACDP2, Ancient Conserved Domain-Containing Protein 2, Metal Transporter CNNM2, Cyclin M2, Cyclin-M2, HOMGSMR, HOMG6

The CNNM2 protein is a transporter for divalent metal cations in the following order of priority: Mg(2+) > Co(2+) > Mn(2+) > Sr(2+) > Ba(2+) > Cu(2+) > Fe(2+). CNNM2 is a member of the family of proteins that contain ancient conserved domains. Members of this protein family contain a cyclin box motif and bear structural similarity to cyclins. CNNM2 may play an important role in magnesium homeostasis by mediating the epithelial transport and renal reabsorption of Mg²⁺. CNNM2 plays a role in brain development and neurological function.

CNNM2 is associated with

• Hypomagnesemia
• Kidney disease and hypomagnesemia
• Seizures
• mental retardation
• Schizophrenia²⁹³
• Depression²⁹³

CNNM2 is one of the three most important genes that integrate with AS3MT. AS3MT rs7085104 is associated with a change in striatal dopamine synthesis capacity.⁹

A study identified CNNM2 as one of the 51 most likely genetic candidates for ADHD.¹⁰

1.324. DLG4 / PSD-95¶

Other names: Discs Large MAGUK Scaffold Protein 4; SAP-90; PSD95; SAP90; PSD-95; Synapse-Associated Protein 90; Discs Large Homolog 4; Disks Large Homolog 4; Discs, Large Homolog 4 (Drosophila); Post-Synaptic Density Protein 95; Postsynaptic Density Protein 95; Tax Interaction Protein 15; MRD62; DLG-4

The DLG4 gene encodes the PSD-95 protein, which is required for the maturation of glutamatergic synapses. It is recruited to NMDA receptor and potassium channel clusters and forms heteromultimers with DLG2, another MAGUK protein. These two MAGUK proteins can interact at postsynaptic sites and form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.²⁹⁴

DLG4 is associated with:

• Intellectual Developmental Disorder, Autosomal Dominant 62
• Dlg4-related synaptopathy

Related signaling pathways:

• Unblocking of NMDA receptors
• Glutamate binding
• Glutamate activation
• RAF/MAP kinase cascade

Paralog: DLG1.

Young nerve cells are far more capable of learning than older nerve cells. The maturation of excitatory synapses into “older” synapses, which result in less learning-capable excitatory neurons, is regulated by, among other factors, PSD-93 and PSD-95 (PSD: postsynaptic density proteins).
The synapses of young neurons contain only active NMDA glutamate receptors, but no active AMPA glutamate receptors. As a result, only very high levels of glutamate can activate young neurons. PSD-95 is required for the maturation of neurons. It activates AMPA receptors, allowing neurons to respond even to lower levels of glutamate. Knocking out PSD-95 restored neuronal plasticity to the level seen in 4-week-old wild-type animals and reduced the number of binocular cells.²⁹⁵ In contrast, PSD-93 prevents neurons from maturing too much and losing their plasticity.²⁹⁶

The DRD4 gene variant with 7 alleles (DRD4.7), which is more common in ADHD, resulted in reduced PSD-95 levels in the PFC in vitro (compared to the DRD4.4 variant, which is less common in ADHD).²⁹⁷ This could potentially help explain the delayed brain maturation typical of ADHD.
Wistar rat pups that received rotenone (an inhibitor of mitochondrial complex I) postnatally exhibited hyperlocomotion, deficits in social interaction, and aversive contextual memory (symptoms of ADHD, ASD, and schizophrenia, all of which are associated with the dopaminergic system). As adult animals, they exhibited alterations in CBP and CREB levels, a decline in mitochondrial biogenesis and Nrf1 expression, as well as altered expression of Rest, Mecp2, and the synaptic proteins PSD-95, synaptotagmin-1, and synaptophysin.²⁹⁸
PSD-95 contributes to the formation of a ternary complex between calcyon and the dopamine D1 receptor, thereby helping to regulate DRD1 trafficking.²⁹⁹
A defect in the DLG-4 gene (which encodes PSD-95) causes a neurological disorder characterized by global developmental delay, intellectual disability, and symptoms of ADHD and ASD.³⁰⁰³⁰¹

1.325. FEZ1¶

Other names: Fasciculation and Elongation Protein Zeta 1; Zygin I; UNC-76; Fasciculation and Elongation Protein Zeta-1; Zygin-1
Do not confuse this with FEZF1.

FEZ1 (Fasciculation and Elongation Protein Zeta 1) encodes a protein.
FEZ1 is associated with:

• Lissencephaly 1
• Schizophrenia

Related signal paths:

• Cytoskeletal Signaling
• Neuroscience
• Binding to the N-terminus of degraded proteins
• Binding of gamma-tubulin

Paralog: FEZ2.

FEZ1 may be involved in axonal growth. In germline transformation experiments, FEZ1 can restore partial motility and axonal fasciculation in C. elegans unc-76 mutants. FEZ1 may be involved in the transport of mitochondria and other cargo along microtubules.³⁰²

The FEZ1 gene is specifically expressed in the nervous system, with expression peaking during neurodevelopment. FEZ1 is involved in various neurodevelopmental processes, such as:³⁰³

• Neurite outgrowth
• dendritic branching
• axonal transport
• neuronal migration

FEZ1 knockout mice show:³⁰³

• Hyperactivity³⁰⁴
• Impulsivity
• Reduced tyrosine hydroxylase expression in the midbrain and brainstem
• Reduced levels of dopamine and norepinephrine, as well as their metabolites, in the nucleus accumbens and PFC
• MPH and guanfacine caused
  • Improves hyperactivity and impulsivity
  • Dopamine and norepinephrine levels in the nucleus accumbens and PFC were restored
  • Increased tyrosine hydroxylase expression

Growth Factors, Neurogenesis¶

1.25. NTF3, neurotrophin 3 (chromosome 12p13.31)¶

Other names: Neurotrophin-3; NGF2; Nerve Growth Factor; Neurotrophic Factor; NGF-2; HDNF; NT-3; NT3

The NTF3 protein belongs to the neurotrophin family, which regulates the survival and differentiation of mammalian neurons. NTF3 is closely related to nerve growth factor and brain-derived neurotrophic factor. NTF3 may be involved in the maintenance of the adult nervous system and may influence neuronal development in the embryo when expressed in the human placenta. NTF3 knockout (KO) mice exhibit severe limb movement disorders. The mature peptide of this protein is identical in all mammals studied, including humans, pigs, rats, and mice. The UniProtKB/Swiss-Prot summary for NTF3 suggests that it promotes the survival of visceral and proprioceptive sensory neurons.³⁰⁵
NTF3 is associated with

• Hypochondriasis
• diabetic polyneuropathy

Related signaling pathways:

• Apoptotic Pathways in Synovial Fibroblasts
• GPCR pathway
• Signal receptor binding
• chemotactic activity

Paralog: NGF

OMIM: Neurotrophin-3 (NTF3) gene

NTF3 is a candidate gene for ADHD.¹¹⁶⁴

1.71. NTF4, NEUROTROPHIN 4 (Chromosome 19q13.33)¶

Other names: NT-4/5; GLC10; NTF5; Neurotrophin 5 (Neurotrophin 4/5); Neurotrophic Factor 4; Neutrophic Factor 4; Neurotrophin-4; Neurotrophin-5; NT-4; NT-5; Neurotrophic Factor 5; GLC10; NT4; NT5

The NTF4 protein is a member of a family of neurotrophic factors, the neurotrophins, which regulate the survival and differentiation of mammalian neurons. The expression of this gene is ubiquitous and is less influenced by environmental signals. While knockouts of other neurotrophins, including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3, are lethal during early postnatal development, NTF4 knockout mice exhibit only minor cellular deficits and develop normally into adulthood. NTF4 is a target-derived survival factor for peripheral sensory sympathetic neurons.³⁰⁶
NTF4 is associated with

• Glaucoma 1, Open-angle, O
• Open-angle glaucoma

Related signaling pathways:

• Pathway of differentiation of pluripotent stem cells
• apoptotic signaling pathway in synovial fibroblasts
• Binding to signal receptors
• Binding to neurotrophin-p75 receptors

Paralog: BDNF

OMIM: NEUROTROPHIN 4; NTF4

NTF4 is a candidate gene for ADHD.¹⁶⁴

1.26. BDNF, Brain-Derived Neurotrophic Factor (Chromosome 11p14.1) (X)¶

OMIM: Brain-derived neurotrophic factor (BDNF) gene

BDNF is a candidate gene for ADHD.¹¹⁶⁴

The BDNF gene is involved in the development of the dopamine D3 receptor (see OMIM entry for DRD3) in the nucleus accumbens during development and adolescence.
In children with ADHD, poorer performance on the Stroop Test for executive functions correlated with the BDNF GG genotype at rs2030324.³⁰⁷ One study found a positive correlation between the BDNF gene polymorphism rs10835210 and ADHD-HI, and a negative correlation between BDNF rs12291186—specifically when one or both alleles were mutated—and ADHD.³⁰⁸

A study found no correlation between the BDNF VAL66MET variant and ADHD in the mainland Chinese population.³⁰⁹

1.27. BAIAP2, Brain-specific angiogenesis inhibitor 1-associated protein¶

OMIM: Brain-specific angiogenesis inhibitor 1-associated protein (BAIAP2) gene

BAIAP2 is a candidate gene for ADHD.¹³¹⁰

1.70. NGF, NERVE GROWTH FACTOR (Chromosome 1p13.2)¶

OMIM: NERVE GROWTH FACTOR

Source¹⁶⁴

1.72. GDNF, GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR (Chromosome 5p13.2)¶

OMIM: GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF

Source¹⁶⁴

1.54. UNC5, C. elegans homolog, B; UNC5B (Chromosome 10q22.1)¶

UNC-5 is a receptor for netrin. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to guide axons, while the other netrin receptor, UNC-40, attracts axons toward the source of netrin production.

OMIM: UNC5, C. elegans, homolog of, B; UNC5B

• SNP: rs16928529; Location: 72652991; In the intron of UNC5B¹⁶⁴
  p: 3.90E−06

1.61. GPC6, GLYPICAN 6 (Chromosome 13q31.3-q32.1)¶

Glypicans are a family of glycosylphosphatidylinositol-anchored heparan sulfate proteoglycans. Glypicans are involved in the regulation of cell growth and cell division. Glypican 6 is a putative cell-surface co-receptor for growth factors, extracellular matrix proteins, proteases, and anti-proteases.
Mutations in glypican 6 are associated with omodysplasia type 1.

OMIM: Glypican 6; GPC6

• SNP: rs7995215 Position: 93206507; In the intron of GPC6¹⁶⁴
  P: 1.35E−08
  A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.232. CNTN5, Contactin 5¶

Other names: HNB-2; NB-2; Neural Recognition Molecule NB-2; Contactin-5; Neural Adhesion Molecule; HNB-2s

The CNTN5 protein is a member of the immunoglobulin superfamily and the contactin family. Contactins mediate cell-surface interactions during the development of the nervous system. CNTN5 is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. CNTN5 may play a role in the formation of axonal connections in the developing nervous system. CNTN5 promotes neurite growth in cerebral cortical neurons, but not in hippocampal neurons. CNTN5 is likely involved in neuronal activity in the auditory system.³¹¹
CNTN5 is associated with

• Coffin-Siris Syndrome 6
• Chromosome 3Pter-P25 deletion syndrome

Paralog: CNTN4

A study identified CNTN5 (variant rs2515376) as one of 96 ADHD candidate genes.¹⁵⁹

Cell Development¶

1.298. POC1B, POC1 Centriolar Protein B¶

Other names: TUWD12; WDR51B; POC1 Centriolar Protein Homolog B; WD Repeat-Containing Protein 51B; Proteome of Centriole Protein 1B; FLJ14923; POC1 Centriolar Protein Homolog B (Chlamydomonas); WD Repeat Domain 51B; CORD20; PIX1; Pix1

POC1B encodes one of the two POC1 proteins found in humans. POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled-coil domain and are components of centrosomes. They play an important role in the formation of the basal body and cilia. POC1B plays an important role in centriole formation and/or stability and in ciliogenesis. POC1B is involved in the early stages of centriole duplication as well as in the later stages of centriole length regulation. POC1B acts in conjunction with POC1A to ensure centriole integrity and the proper formation of the mitotic spindle. POC1B is required for the formation of primary cilia, cilia length, and cell proliferation. POC1B is required for retinal integrity.³¹²
POC1B is associated with

• Cone-Rod Dystrophy 20
• Cone-Rod Dystrophy 2

Related signal paths:

• Ciliopathies

Paralog: POC1A

This gene was identified as a candidate for ADHD in a large-scale GWAS.¹⁹³

1.62. CTNNA2, CATENIN ALPHA-2 (Chromosome 2p12)¶

Other names: CAP-R; CT114; Catenin (Cadherin-Associated Protein), Alpha 2; Cadherin-Associated Protein, Related; Alpha-Catenin-Related Protein; Cancer/Testis Antigen 114; Alpha-N-Catenin; Catenin Alpha-2; CAPR; Alpha N-Catenin; CDCBM9; CTNR

The CTNNA2 protein mediates actin filament binding. It is involved in the following functions:

• Inhibition of Arp2/3-complex-mediated actin nucleation and Arp2/3-mediated actin polymerization In this way, CTNNA2 suppresses excessive actin branching, which would impair the growth and stability of neurites.³¹³
• Regulation of neuronal migration / development of the nervous system
• Regulation of the development of neuronal projections
• Acts as a link between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system.
• Regulation of cortical neuronal migration and neurite growth.
• Regulation of the morphological plasticity of synapses and the lamination of the cerebellum and hippocampus during development.
• Control of fear modulation.

CTNNA2 is associated with the following clinical presentations:

• Complex cortical dysplasia with other brain malformations 9 (CDCBM9)
• Hereditary Breast and Ovarian Cancer Syndrome

OMIM: CATENIN, ALPHA-2

• SNP: rs13395022 Position: 79735768; In the intron of CTNNA2¹⁶⁴
  p: 9.68E−06

Circadian Rhythm¶

The circadian clock, an internal timing system, regulates various physiological processes by generating approximately 24-hour circadian rhythms in gene expression, which are reflected in rhythms in metabolism and behavior. The circadian system is a key regulator of a wide range of physiological functions, including metabolism, sleep, body temperature, blood pressure, and endocrine, immunological, cardiovascular, and renal functions. The circadian system consists of two main components: the central clock, located in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks, which are found in nearly all tissues and organ systems. Both the central and peripheral clocks can be reset by environmental cues, also known as time signals. The primary time signal for the central clock is light, which is detected by the retina and transmitted directly to the SCN. The central clock controls the peripheral clocks via neural and hormonal signals, body temperature, and feeding-related signals, ensuring that all clocks are synchronized with the external light-dark cycle. Circadian rhythms enable an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression so that a peak in protein expression is reached every 24 hours, thereby controlling when a specific physiological process is most active in relation to the solar day. The transcription and translation of key clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1, and CRY2) plays a crucial role in rhythm formation, while delays caused by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the duration of a complete cycle). A diurnal rhythm is synchronized with the day-night cycle, while ultradian and infradian rhythms have periods shorter and longer than 24 hours, respectively. Disorders in circadian rhythms contribute to the pathogenesis of cardiovascular diseases, cancer, metabolic syndromes, and aging. A transcription-translation feedback loop (TTFL) forms the core of the circadian clock’s molecular mechanism. The transcription factors CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2 form the positive arm of the feedback loop; they act as a heterodimer and activate the transcription of core clock genes and clock-regulated genes (which are involved in important metabolic processes) that contain E-box elements (5’-CACGTG-3’) in their promoters. The most important clock genes—PER1/2/3 and CRY1/2— which are transcription repressors, form the negative arm of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer by inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates the nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and activate or suppress ARNTL/BMAL1 transcription, respectively.³¹⁴

1.29. CLOCK, Clock Circadian Regulator (Chromosome 4q12) (x)¶

Other names: BHLHe8; Circadian Locomoter Output Cycles Protein Kaput; KIAA0334; KAT13D; Class E Basic Helix-Loop-Helix Protein 8; EC 2.3.1.48; Circadian Locomotor Output Cycles Kaput Protein; Clock (Mouse) Homolog; Clock Homolog (Mouse); EC 2.3.1.48’); Clock Homolog; BHLHE8; HCLOCK

The CLOCK protein plays a central role in the regulation of circadian rhythms. CLOCK encodes a transcription factor of the bHLH (basic helix-loop-helix) family and possesses DNA-binding histone acetyltransferase activity. CLOCK forms a heterodimer with ARNTL (BMAL1), which binds to E-box enhancer elements upstream of the Period (PER1, PER2, PER3) and cryptochrome (CRY1, CRY2) genes and activates the transcription of these genes. PER and CRY proteins form heterodimers and suppress their own transcription by interacting with CLOCK/ARNTL complexes in a feedback loop. CLOCK regulates the circadian expression of ICAM1, VCAM1, CCL2, THPO, and MPL and also acts as an enhancer of the transactivation potential of NF-kappaB. CLOCK plays an important role in the homeostatic regulation of sleep. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10, as well as genes involved in glucose and lipid metabolism. CLOCK promotes the rhythmic opening of chromatin and regulates DNA accessibility for other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1. The preferred binding motif for the CLOCK-ARNTL/BMAL1 heterodimer is 5’-CACGTGA-3’, which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence. (CLOCK; GeneCards.org))
Clock acts as a transcriptional repressor of tyrosine hydroxylase, which is involved in dopamine synthesis.³¹⁵
CLOCK is associated with

• delayed sleep phase disorder
• Narcolepsy
• Behavioral changes in certain populations
• Obesity
• metabolic syndrome

Paralog: NPAS2

OMIM: Circadian Locomotor Output Cycles Protein Kaput (CLOCK) gene

CLOCK is a candidate gene for ADHD.¹
The gene variants of the AA and AG genotypes of rs1801260 were significantly correlated with ADHD. Similarly, the rs1801260 polymorphism is a risk factor for ADHD.³¹⁶ Increased expression of CLOCK, PER1, lncRNA HULC, and lncRNA UCA1 correlated with
evening chronotype, difficulty falling asleep and staying asleep, disorders in the sleep-wake transition, and excessive sleepiness in ADHD. There was no significant association between individual genes and specific sleep parameters.³¹⁷

1.261. PER1, Period Circadian Regulator 1 (Chromosome 2q37.3)¶

Other names: RIGUI; PER; Period Circadian Protein Homolog 1; Circadian Clock Protein PERIOD 1; Period Circadian Clock 1; HPER1; Circadian Pacemaker Protein RIGUI; Circadian Pacemaker Protein Rigui; Period, Drosophila, Homolog Of; Period (Drosophila) Homolog 1; Period Homolog 1 (Drosophila); Period Homolog 1; KIAA0482; HPER

PER1 belongs to the Period gene family and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. The genes in this family encode components of the circadian rhythms of motor activity, metabolism, and behavior.
PER1 is upregulated by CLOCK/ARNTL heterodimers, but this upregulation is then suppressed in a feedback loop by PER/CRY heterodimers that interact with CLOCK/ARNTL. PER1 is a transcription repressor that forms a core component of the circadian clock.
PER1 regulates the expression of circadian target genes at the post-transcriptional level, but may not be required for repression at the transcriptional level. PER1 controls PER2 protein degradation. PER1 represses CRY2, thereby preventing its suppression of CLOCK/ARNTL target genes such as FXYD5 and SCNN1A in the kidney and PPARA in the liver. In addition to its role in maintaining the circadian clock, PER1 plays an important role in regulating various processes. PER1 is involved in suppressing glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR with glucocorticoid response elements (GREs) mediated by ARNTL:CLOCK. PER1 plays a role in modulating the neuroinflammatory state by regulating the release of inflammatory mediators, such as CCL2 and IL-6. In spinal astrocytes, PER1 inhibits the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NF-κB. PER1 coordinately regulates the expression of several genes involved in the regulation of renal sodium reabsorption. PER1 can act as a gene- and tissue-specific activator of gene expression; in the kidney, PER1 increases the expression of WNK1 and SLC12A3 in collaboration with CLOCK. PER1 modulates the hair follicle cycle. PER1 represses (suppresses) the CLOCK-ARNTL/BMAL1-induced transcription of BHLHE40/DEC1.³¹⁴
PER1 is associated with

• Corticosteroid-Binding Globulin Deficiency
• REM Sleep Behavior Disorder
• Cancer

Related signal paths:

• Melatonin Metabolism and Effects
• circadian clock
• Binding of transcription factors
• sequence-specific DNA binding in the cis-regulatory region of RNA polymerase II

Paralog: PER2

The PER2 gene was identified as a candidate gene for ADHD in a 2008 study. It is believed to correlate with general ADHD symptoms.²⁰ Increased expression of CLOCK, PER1, lncRNA HULC, and lncRNA UCA1 correlated with
evening chronotype, difficulty falling asleep and staying asleep, disorders in the sleep-wake transition, and excessive sleepiness in ADHD. There was no significant association between individual genes and specific sleep parameters.³¹⁷

1.47. PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2 (Chromosome 2q37.3)¶

OMIM: PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2

In a 2006 study, the PER2 gene was identified as a candidate gene for ADHD with a p-value of 0.017.³

1.73. Vasoactive Intestinal Peptide Receptor 2; VIPR2 (Chromosome 7q36.3)¶

VIPR2 and VIPR1 (192321) encode receptors for the neuropeptide vasoactive intestinal peptide (VIP; 192320) and also bind pituitary adenylate cyclase-activating polypeptide (PACAP; 102980) with the same affinity as VIP.

The human VIP2 receptor binds to PACAP38, PACAP27, VIP, and Heldermin, each of which activates adenylate cyclase. GTP inhibits the binding of the peptide.

Food intake triggers a neural signal from the gut that induces antimicrobial and metabolic responses. This signal is regulated by innate lymphoid cells type 3 (ILC3). Food intake rapidly activates a population of gut neurons that produce VIP. Projections from VIP-producing neurons in the lamina propria are located in close proximity to clusters of ILC3 that selectively express VIPR2. VIPR2 inhibits IL-22 synthesis. The consequences are that the levels of antimicrobial peptides derived from epithelial cells are reduced, while the expression of lipid-binding proteins and transporters is increased. During food intake, the activation of VIP-producing neurons thus promotes the growth of segmented filamentous bacteria associated with the epithelium and increases lipid absorption. This establishes a diet- and circadian-regulated dynamic neuroimmune cycle in the gut that mediates the relationship between IL-22-mediated innate immune protection and the efficiency of nutrient absorption.

Rare copy number variants (CNVs) of VIPR2 are associated with schizophrenia—
Microduplications of 7q36.3 were associated with increased VIPR2 transcription and increased cyclic AMP signaling.

Vipr2 -/- mice (VPR2-KO mice) are unable to maintain normal circadian rhythms of rest/activity behavior and show no circadian expression of the central clock genes Per1 (602260), Per2 (603426), and Cry1 (601933), nor do they exhibit circadian expression of the clock-regulated gene encoding arginine vasopressin (AVP; 192340) in the suprachiasmatic nuclei. Furthermore, VPR2-KO mice showed no acute induction of Per1 and Per2 by nocturnal illumination.

OMIM: Vasoactive Intestinal Peptide Receptor 2; VIPR2

Source⁵⁶

1.79. KAT2B, LYSINE ACETYLTRANSFERASE 2B¶

The protein KAT2B (lysine acetyltransferase 2B) is involved in:³¹⁸

• Signaling pathways of apoptosis in synovial fibroblasts
• Signal transduction pathway involved in the regulation of activated PAK-2p34 through proteasome-mediated degradation
• Protein kinase binding
• KAT2B is a histone acetyltransferase (HAT) and thus enhances transcriptional coactivator activity
• Exhibits significant histone acetyltransferase activity with nuclear histones (H3 and H4) as well as with nucleosome core particles
• Also acetylates non-histone proteins, such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K, and TBX5
• Inhibits cell cycle progression and counteracts the mitogenic activity of the adenoviral E1A oncoprotein
• Acts as a circadian transcriptional coactivator that enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers
• Acetylation of TBX5, thereby contributing to the development of the heart and limbs
  • Acetylation regulates the nucleocytoplasmic shuttling of TBX5
• inhibits centrosome amplification by mediating the acetylation of PLK4
• Acetylates RRP9/U3-55K, a key subunit of the U3 snoRNP complex, thereby impairing the processing of pre-rRNA
• Acetylates MAPRE1/EB1, thereby promoting dynamic kinetochore-microtubule interactions during early mitosis
• Acetylated spermidine
• is recruited by the viral Tat protein during HIV-1 infection. It regulates the transactivating activity of Tat and may help induce chromatin remodeling of proviral genes.

KAT2B is associated with the following diseases:

• Holt-Oram syndrome
• Spinocerebellar Ataxia 7

OMIM: KAT2B, LYSINE ACETYLTRANSFERASE 2B

KAT2B is a candidate gene for ADHD.³¹⁹

1.84. CADM1, CELL ADHESION MOLECULE 1 (TSLC1, IGSF4); CADM2, CELL ADHESION MOLECULE 2¶

Other names: SYNCAM; IGSF4A; NECL2; Tumor Suppressor in Lung Cancer 1; Necl-2; RA175; IGSF4; TSLC1; ST17; BL2; Spermatogenic Immunoglobulin Superfamily; Immunoglobulin Superfamily Member 4; Synaptic Cell Adhesion Molecule; Nectin-Like Protein; Nectin-Like 2; SYNCAM1; TSLC-1; Immunoglobulin Superfamily, Member 4; TSLC1/Nectin-Like 2/IGSF4; STSLC-1; SynCAM1; SgIGSF; NECL-2; SgIgSF; SynCAM; IgSF4

The CADM1 protein mediates signal receptor binding. CADM1 is involved in:³²⁰

• Cell detection
• upregulation of cytokine production
• promotes the cytotoxicity of natural killer (NK) cells
• promotes the secretion of interferon-gamma (IFN-gamma)
• Regulation of cell adhesion (cell-to-cell connections).
• essential for the survival of mast cells
• mediates binding to and communication with nerves in mast cells
• acts as a synaptic cell adhesion molecule
• plays a role in the formation of dendritic spines and in synapse development
• May be involved in neuronal migration, axon growth, pathfinding, and fasciculation along the axons of differentiating neurons
• is located in the plasma membrane
• is used to treat breast cancer and prostate cancer.

SynCAM1 is an adhesion molecule involved in synaptic differentiation and organization. SynCAM1 is also expressed in astroglial cells, where it mediates adhesive communication between astrocytes and between glial cells and neurons. In astrocytes, SynCAM1 is functionally linked to erbB4 receptors, which are involved in regulating both neuronal/glial development and mature neuronal and glial function.³²¹

CADM1 is associated with:

• Cervical Carcinoma In Situ
• Retroperitoneal fibrosis

Paralog: CADM2
Certain variants of the CADM2 gene are associated with hyperactivity.³²²

OMIM: CADM1, CELL ADHESION MOLECULE 1

In a study, the CADM1 rs10891819 genotype (T allele) was negatively correlated with errors on the Stroop test, and thus positively correlated with inhibitory control, suggesting it has a protective effect against ADHD.³²³ Silencing CADM1 in astrocytes in mice causes ADHD symptoms. The mice also exhibited these symptoms during the day (during the light phase of the light-dark cycle), suggesting that their circadian pattern of motor and/or sleep activity was disrupted. The mice further exhibited persistent, aimless exploratory behavior in familiar surroundings, as well as increased impulsivity and aggression (a tendency to jump out of the cage when the cage lid was opened and to attack other animals or the person opening the cage without provocation).³²¹

CRY1¶

People with ADHD (often?) carry a mutation in the central circadian gene CRY1 (c. 1657 + 3A > C), which leads to a deletion of exon 11 in the CRY1 protein (CRY1Δ11), causing them to exhibit typical ADHD symptoms.
Cry1Δ11 (c. 1717 + 3A > C) mice exhibit ADHD-like symptoms:³²⁴

• Hyperactivity
• Impulsivity
• Learning deficits
• Memory deficits
• hyperactive cAMP signaling pathway in the nucleus accumbens
• Upregulated c-Fos, localized primarily in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc
• increased neuronal excitability of DRD1-MSNs in the nucleus accumbens
• Unlike the WT CRY1 protein, the CRY1Δ11 protein was mechanistically unable to interact with the Gαs protein and inhibit DRD1 signaling
• The DRD1 antagonist SCH23390 normalized most ADHD-like symptoms

1.375. BMAL1¶

BMAL1 is a key circadian gene.
Knocking out BMAL1 in dopaminergic neurons leads to ADHD-like symptoms in male mice due to hyperactive dopamine signaling, such as³²⁵

• Hyperactivity
• Attention problems
• Working memory problems

Bmal1-cKO mice exhibited increased dopamine release and increased neuronal excitability in striatal neurons. Amphetamine and the D1 receptor antagonist SCH23390 reduced this hyperactivity.

Bmal1 is also found in astrocytes, which regulate the circadian rhythm of neurons and are also involved in maintaining the balance of dopamine and norepinephrine at the synaptic cleft.

1.341. Neuropeptide Y (NPY)¶

The neuropeptide Y (NPY) gene was identified as a candidate CNV in a study of 99 children and adolescents with severe ADHD. The study used genome-wide screening for copy number variations (CNVs) to detect microdeletions and microduplications that might play a role in the pathogenesis of ADHD.³²⁶ Reduced activation of the left ventral striatum and the left posterior insula during the anticipation of large rewards or losses, as measured by functional magnetic resonance imaging, linked the gene dose-dependent increases in NPY with reward and emotion processing in duplication carriers.

NPY signals from the lateral geniculate body (intergeniculate leaflet) to the suprachiasmatic nucleus (SCN) play a key role in the non-photic regulation of the internal clock. NPY is involved in the phase shift of circadian rhythms in the SCN and rapidly reduces the mRNA levels of the core genes Period 1 and Period 2. NPY-deficient mice exhibit altered entrainment properties.^327328329

2.52. MTA3, METASTASIS-ASSOCIATED GENE 3 (Chromosome 2)¶

Other names: Metastasis-Associated 1 Family Member 3; KIAA1266; Metastasis-Associated Gene Family, Member 3; Metastasis-Associated Protein MTA3

The MTA3 protein appears to be associated with the cell cycle.
MTA3 is thought to activate histone deacetylase-binding activity, transcriptional coactivator activity, and transcriptional corepressor activity. MTA3 is involved in the negative regulation of DNA-templated transcription. MTA3 is located in the nucleoplasm and is part of the NuRD complex. MTA3 plays a role in maintaining normal epithelial architecture by suppressing SNAI1 transcription in a histone deacetylase-dependent manner and thereby regulating E-cadherin levels. MTA3 contributes to transcriptional repression mediated by BCL6.³³⁰
MTA3 is associated with

• Pyloric stenosis
  • Narrowing of the stomach outlet
• Hutchinson-Gilford progeria syndrome
  • a severe aging process (progeria) affecting the skin, skeleton, and blood vessels, which begins in early childhood

Related metabolic pathways:

• Signal transduction
• DNA-binding transcription factor activity
• Chromatin binding

Paralog: MTA1

OMIM: METASTASIS-ASSOCIATED GENE 3; MTA3

• SNP: rs930421; Position: 42834743; Exon of MTA3 ¹⁶⁴
  p: 5.64E−06
  Associated with all ADHD symptoms
• SNP: rs6719977 Position: 42839307; Within 2 kb downstream of MTA3 ¹⁶⁴
  p: 1.67E−06
  Associated with hyperactivity and impulsivity

MTA3 (Metastasis-Associated 1 Family Member 3, 2.52) may have a circadian influence. The circadian connection is well established for family member MTA1, which is an integral component of the circadian molecular machinery: the CLOCK–BMAL1 heterodimer activates MTA1 transcription via an E-box element; MTA1, in turn, recruits CLOCK–BMAL1 to its own promoter as well as to the CRY1 promoter. An MTA1 knockout disrupts the free-running period and normal entrainment in mice.

Immune System¶

1.57. CSMD2, CUB AND SUSHI MULTIPLE DOMAINS 2 (Chromosome 1p35.1)¶

The CSMD2 protein appears to be involved in regulating the immune system’s complement cascade. It may act as a tumor suppressor for colorectal cancer. Genetic defects are associated with schizophrenia.

OMIM: CUB AND SUSHI MULTIPLE DOMAINS 2

• SNP: rs2281597 Position: 34132445; In the intron of CSMD2¹⁶⁴
  p: 5.41E−07
  A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.112. TRIM26, Tripartite Motif Containing 26¶

Other names: RNF95, ZNF173, Tripartite Motif-Containing Protein 26, Zinc Finger Protein 173

The TRIM26 protein is a member of the TRIM (tripartite motif) family. The TRIM motif comprises three zinc-binding domains—a RING domain, a B-box type 1 domain, and a B-box type 2 domain—as well as a coiled-coil region. TRIM26 is found in cytoplasmic bodies. The RING domain suggests that TRIM26 may have DNA-binding activity. TRIM26 is an E3 ubiquitin protein ligase that regulates IFN-beta production and the antiviral response downstream of various DNA-encoded pattern recognition receptors (PRRs). TRIM26 promotes the ubiquitination of nuclear IRF3 and its proteasomal degradation. TRIM26 interacts with TBK1 and NEMO during the innate response to a viral infection, leading to the activation of TBK1.

TRIM26 is associated with neural tube defects.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.210. MYO1G, Myosin IG¶

Other names: Minor Histocompatibility Antigen HA-2; Unconventional Myosin-Ig; HA-2; HA2; Myosin-Ig; HLA-HA2; MHAG

The MYO1G protein is a class I myosin associated with the plasma membrane and is abundant in T and B lymphocytes and mast cells.
MYO1G is an unconventional myosin that is required during the immune response for the recognition of rare antigen-presenting cells by regulating T-cell migration. Unconventional myosins are actin-based motor proteins with ATPase activity that facilitate intracellular movement.
MYO1G acts as a regulator of T-cell migration by generating a membrane tension that forces the cell to meander, thereby improving the detection of rare antigens during lymph node surveillance, which enables the eradication of pathogens. MYO1G is also essential in B cells, where it regulates various membrane- and cytoskeleton-dependent processes. MYO1G is involved in phagocytosis mediated by the Fc-gamma receptor.
MYO1G encodes the minor histocompatibility antigen HA-2. More generally, minor histocompatibility antigens (mHags) are immunogenic peptides that, when complexed with MHC, can trigger an immune response upon recognition by specific T cells. The peptides originate from polymorphic intracellular proteins that are cleaved via the normal pathways of antigen processing. The binding of these peptides to MHC class I or class II molecules and their expression on the cell surface can trigger a T-cell response, thereby causing graft rejection or graft-versus-host disease (GVHD) following a hematopoietic stem cell transplant from HLA-identical sibling donors.³³¹
MYO1G is associated with

• Graft-versus-host disease. This is a common complication following a bone marrow transplant (BMT) due to a mismatch in minor histocompatibility antigens in HLA-identical sibling bone marrow transplants.

Paralog: MYO1D

A study identified MYO1G (variant rs6958168) as one of 96 ADHD candidate genes.¹⁵⁹

1.230. TLR4, Toll-like receptor 4¶

Other names: HToll; Toll-like receptor 4; ARMD10; CD284; TLR-4; Toll-like receptor 4 protein; homolog of Drosophila Toll; CD284 antigen; TOLL

The TLR4 protein belongs to the family of Toll-like receptors (TLRs), which play a fundamental role in the recognition of pathogens and the activation of the innate immune system. TLRs typically exist as homodimers (heterodimers have been reported) and are found on immune cells, macrophages, B lymphocytes, and mast cells. TLRs are highly conserved from Drosophila to humans and exhibit structural and functional similarities. They recognize pathogen-associated molecular patterns expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different expression patterns. In silico studies have shown that surface TLR4 binds particularly strongly to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19). This receptor is also involved in signal transduction triggered by lipopolysaccharide (LPS), which is present in most Gram-negative bacteria. TLR4 cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). TLR4 acts via MYD88, TIRAP, and TRAF6, and activates NF-kappa-B, cytokine secretion, and the inflammatory response. TLR4 is involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). The reactions triggered by Ni(2+) require non-conserved histidines and are therefore species-specific. Both M. tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression. TLR4, in complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is triggered by the binding of oxLDL or amyloid-beta 42 to CD36. This event induces the formation of a heterodimer consisting of TLR4 and TLR6, which is rapidly internalized and triggers an inflammatory response leading to NF-kappa-B-dependent production of the cytokines CXCL1, CXCL2, and CCL9 via the MYD88 signaling pathway and the cytokine CCL5 via the TICAM1 signaling pathway, as well as to the secretion of IL1B. TLR4 binds electronegative LDL (LDL(-)) and mediates the LDL(-)-induced cytokine release. In vitro stimulation of monocytes with M. tuberculosis PstS1 induces the activation of p38 MAPK and ERK1/2 primarily via TLR2, but also partially via the TLR4 receptor. TLR4 is activated by the signaling regulator NMI, which acts as a damage-associated molecular pattern (DAMP) in response to cellular injury or pathogen invasion, thereby promoting the activation of the nuclear factor NF-kappa-B.³³²
TLR4 is associated with

• Age-related macular degeneration 10
• Pyelonephritis
• Differences in LPS sensitivity

Paralog: TLR7

A study identified TLR4 (variant rs10121605) as one of 96 candidate genes for ADHD.¹⁵⁹

Stress Systems¶

HPA axis¶

1.74. NR3C1, Nuclear Receptor Subfamily 3 Group C Member 1, Glucocorticoid Receptor (Chromosome: 5q31.3)¶

Other names: GR; Glucocorticoid Receptor; GRL; Nuclear Receptor Subfamily 3, Group C, Member 1 (Glucocorticoid Receptor); Nuclear Receptor Subfamily 3, Group C, Member 1 Variant HGR-B(54); Nuclear Receptor Subfamily 3, Group C, Member 1 Variant HGR-B(77); Nuclear Receptor Subfamily 3, Group C, Member 1 Variant HGR-B(93); Nuclear Receptor Subfamily 3, Group C, Member 1; GCRST; GCCR; GCR

OMIM: NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1; NR3C1 (GLUCOCORTICOID RECEPTOR; GCCR; GR GCR; GRL)

The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 results in increased GRβ expression³³³ and has been associated with ADHD.³³⁴ However, the GRβ variant does not bind cortisol, is transcriptionally inactive, and is considered a dominant-negative inhibitor of the functional GRα variant.³³⁵
The GR-9β-stabilizing polymorphism has been associated with an increased ACTH and cortisol stress response.³³⁶

The combined inhibitory effect of the GR-9β haplotype and stress exposure can reduce GR activity to a pathologically low level, thereby contributing to ADHD-related behavior. The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with an increased risk of ADHD. In carriers of this haplotype, stress and ADHD severity correlate more strongly than in non-carriers. This gene-environment interaction was further amplified when the people with ADHD were also homozygous for the 5-HTTLPR L allele rather than the S allele.³³⁷

In contrast, the Bcll GG haplotype of the GR was associated with a blunted cortisol stress response in men and a markedly elevated cortisol stress response in women (all of whom were using hormonal contraception).³³⁶

1.75. FKBP5, FK506-BINDING PROTEIN 5 (Chromosome 6p21.31)¶

OMIM: FK506-BINDING PROTEIN 5; FKBP5

The FKBP5 gene modulates the sensitivity of the glucocorticoid receptor.
With regard to the damage caused by long-term stress, there is a significant difference depending on whether the stress occurs during the brain’s developmental phase or in adulthood. Downregulation in adulthood has fewer long-term consequences. The epigenetic demethylation of the FKBP5 gene, which modulates the sensitivity of glucocorticoid receptors,³³⁸ is mediated by stress only during the differentiation and proliferation phases of neurons (i.e., during childhood and adolescence), but not in mature neurons (i.e., in adults).³³⁹

The FKBP5 gene polymorphisms rs1360780, rs4713916, and rs3800737 result in elevated FKBP51 concentrations in the blood and, consequently, an enhanced cortisol response to psychosocial stress. Downregulation of the HPA axis is slowed and remains incomplete for an extended period, even with repeated exposure to stress. In contrast, the FKBP5 gene polymorphism Bcl1 is associated with an anticipatory cortisol response to psychosocial stress.³⁴⁰

1.60. CDH23, CADHERIN 23 (Chromosome 10q22.1)¶

The CDH23 gene encodes a member of the cadherin superfamily, which comprises calcium-dependent cell-cell adhesion glycoproteins.
CDH23 is associated with pituitary adenomas (second increment of the HPA axis). Pituitary adenomas have a prevalence of 14 to 22%.³⁴¹

OMIM: CADHERIN 23

The CDH23-SNP rs11594082, located at position 72969259 in the intron of CDH23, is a candidate gene for ADHD.¹⁶⁴
p: 1.00E−05

1.254. NAT2, N-acetyltransferase 2¶

Other names: Arylamine N-acetyltransferase 2; AAC2; N-acetyltransferase 2 (Arylamine N-acetyltransferase) 2; N-acetyltransferase Type 2; Arylamide Acetylase 2; EC 2.3.1.5; NAT-2; PNAT; Polymorphic Arylamine N-Acetyltransferase

The NAT2 protein is an enzyme responsible for the activation and inactivation of arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism, in which human populations are divided into fast, intermediate, and slow acetylator phenotypes. NAT2 is involved in the detoxification of a wide variety of hydrazine and arylamine drugs. NAT2 catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is capable of bioactivating several known carcinogens.

NAT2 is associated with

• Acetylation, slow
  • Among other things, NAT2 acetylates³⁴²
    • Sulfanilamides
    • Chloramphenicol
    • Glucocorticoids
• multiple chemical sensitivity
• Cancer
• Drug toxicity

Related metabolic pathways:

• Caffeine Trail
• Pharmacokinetics
• Paracetamol ADME

Paralog: NAT1

A study identified NAT2 (variant rs12676224) as one of 96 candidate genes for ADHD.¹⁵⁹
The NAT2 genotypes rr and rs are phenotypically rapid excretors. Drugs that must be acetylated for excretion (such as glucocorticoids) are often ineffective or result in treatment resistance in rapid excreters, while slow excreters are more prone to adverse effects.³⁴² Since glucocorticoids are necessary for the downregulation of the HPA axis following a stress response, we consider it conceivable that NAT2-rr and -rs carriers may have a higher risk of HPA axis shutdown problems, which (as evident from the ADHD model in SHR rats) can lead to ADHD-C symptoms.

Oxidative Stress¶

1.297. DUSP6, Dual-Specificity Phosphatase 6¶

Other names: PYST1; MKP-3; Mitogen-Activated Protein Kinase Phosphatase 3; Dual Specificity Protein Phosphatase PYST1; Dual-Specificity Protein Phosphatase 6; MAP Kinase Phosphatase 3; MKP3; Serine/Threonine-Specific Protein Phosphatase; EC 3.1.3.16; EC 3.1.3.48; HH19

The DUSP6 protein belongs to the subfamily of dual-specificity protein phosphatases. These phosphatases inactivate their target kinases by dephosphorylating both phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein kinase (MAPK/ERK, SAPK/JNK, p38) superfamily, which are involved in cell proliferation and differentiation. Various members of the dual-specificity phosphatase family exhibit different substrate specificities for various MAP kinases, different tissue distributions and subcellular localizations, as well as different patterns of inducibility of their expression by extracellular stimuli.
DUSP6 inactivates MAP kinases, particularly ERK2. DUSP6 is expressed in many tissues, especially in the heart and pancreas. Unlike most other members of this family, DUSP6 is localized in the cytoplasm.
DUSP6 plays an important role in alleviating chronic postoperative pain. DUSP6 is necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and p38 MAP kinase induced by peripheral surgery, which leads to the resolution of acute postoperative allodynia. DUSP6 is important for the dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to the resolution of acute pain. DUSP6 promotes cell differentiation by regulating MAPK1/MAPK3 activity and the expression of AP1 transcription factors.³⁴³
DUSP6 is associated with

• Hypogonadotropic hypogonadism 19 with or without anosmia
• Normosmolar congenital hypogonadotropic hypogonadism

Related signaling pathways:

• MyD88-dependent cascade initiated at the endosome
• Endometrial cancer
• Phosphatase activity
• Phosphoprotein phosphatase activity

Paralog: DUSP7

A study using 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats found that dioscin might help with Parkinson’s disease because it

• drastically improved the viability of the cells
• reduced the levels of reactive oxygen species (ROS)
• improved motor skills
• Elevated tyrosine hydroxylase (TH) levels
• restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats.
  Possible mechanisms underlying the effects of diospin included, among others, an increase in DUSP6 expression levels (1.87-fold in cells and 2.56-fold in rats) and a regulation of DUSP6 that modulated the Keap1/Nrf2 signaling pathway. Dioscin protected against oxidative stress via the DUSP6 signaling pathway.³⁴⁴

The MAPK phosphatase MKP3/DUSP6 is an inhibitor of mitogen-activated protein kinase (MAPK) and prevents the depolarization-dependent release of dopamine in rat PC12 cells.³⁴⁵

DUSP6 was identified as an ADHD candidate gene in a large-scale GWAS.¹⁹³
DUSP6 has been identified as a candidate gene for ADHD.²⁹¹.

Other Consequences of Stress¶

1.108. NCL, Nucleolin¶

Other names: Nsr1, C23, Protein C23

NCL is the most important eukaryotic nucleolar phosphoprotein and is involved in the synthesis and maturation of ribosomes. It is located primarily in dense fibrillar regions of the nucleolus. NCL induces chromatin decondensation by binding to histone H1. NCL appears to play a role in pre-rRNA transcription and ribosome assembly and is involved in the process of transcription elongation. NCL is involved in a surprisingly large number of molecular processes; it interacts with many types of molecules and regulates many aspects of DNA and RNA metabolism.

Nucleolin (and ELAVL1) interact independently with MBII-52 snoRNA via co-immunoprecipitation.
snoRNAs are small nucleolar RNAs and are among the most abundant types of noncoding RNA in all organisms. They are essential for the maturation of pre-ribosomal RNA (pre-rRNA) in the nucleolus. Unlike known snoRNAs, brain-specific snoRNAs lack complementarity to pre-rRNAs or pre-snRNAs, which is why they are referred to as “orphan snoRNAs.” Unlike canonical snoRNAs, which target snRNAs or rRNAs, the orphan snoRNA MBII-52 exhibits an 18-nucleotide-long complementarity to the pre-mRNA of the serotonin 2C receptor and thereby reduces its mRNA expression.³⁴⁶

NCL³⁴⁷

• is a histone chaperone and chromatin remodeler involved in DNA repair, replication, and recombination.
• is involved in the transcription and maturation of ribosomal RNA, as well as in the assembly and transport of ribosomes.
• is involved in the transcription, splicing, stability, transport, and translation of many mRNAs.
• contributes to the anchoring of microtubules to the centrosomes in the cytosol of interphase cells and to microtubule polymerization.
• regulates the assembly and interaction of Ras proteins at the plasma membrane, as well as MAPK signal transduction.
• acts as a co-receptor for cytokines, growth factors, and matrix proteins on the cell surface
• has consequences for numerous pathologies.
• involved in³⁴⁸
  • Cell proliferation
  • Angiogenesis
  • Apoptosis regulation
  • Stress Response
  • microRNA processing

NCL is affiliated with

• Ependymoma in childhood
• Spinal Muscular Atrophy
• Cancer
• Viral diseases
• neurodegenerative diseases

Stress conditions such as heat shock, γ-irradiation, and camptothecin treatmentcan cause a dramatic redistribution of NCL from the nucleolus to the nucleoplasm in a p53-dependent manner. This can temporarily impair DNA replication and repair. The interaction between stress-activated nucleoplasmic p53 and NCL prevents p53 from being imported into the nucleolus, leading to its accumulation in the nuclear matrix. Following stress stimulation, NCL can undergo a specific posttranslational modification, such as serine phosphorylation by casein kinase II, which promotes the interaction of NCL with RPA (replication protein A), resulting in its accumulation in the nucleoplasm, since the nucleoplasm contains a large amount of RPA. This redistribution is associated with increased formation of the NCL-RPA complex, which further inhibits initiation and elongation during DNA replication.

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰
Another study identified NCL (variant rs16828074) as the most likely of 96 candidate genes.¹⁵⁹

Broad-spectrum mechanisms¶

Transcription¶

1.95. RERE¶

The RERE protein is essential for normal prenatal development. A deficiency in RERE function likely alters the activity of many genes involved in prenatal development. These changes prevent the normal development of tissue in the brain, eyes, heart, and other organs. The RERE protein interacts with other proteins, known as transcription factors, which control the activity (transcription) of specific genes. The RERE protein helps these transcription factors turn on (activate) and deactivate (suppress) a range of genes that are important for early development, thereby ensuring that the genes are activated (expressed) at the right time and in the right place for proper tissue formation. Research findings suggest that the RERE protein plays a role in the development of the brain, eyes, inner ear, heart, and kidneys.³⁴⁹

A study identified RERE as one of the 51 most likely candidate genes for ADHD.¹⁰

1.45. HES1; HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1 (Chromosome 3q29)¶

The HES1 protein belongs to the bHLH (basic helix-loop-helix) family of transcription factors. It is a transcriptional repressor of genes that require a bHLH protein for their transcription. As a member of the bHLH family, it is a transcriptional repressor that influences cell proliferation and differentiation during embryogenesis. HES1 regulates its own expression via a negative feedback loop and oscillates with a period of approximately 2 hours.

OMIM: HAIRY/ENHANCER OF SPLIT, DROSOPHILA, HOMOLOG OF, 1; HES1

The HES1 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.016.³

1.86. FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1¶

Do not confuse this with FEZ1.

The FEZF1 protein is a transcription repressor. In mice, FEZF1 is expressed in the forebrain during early embryonic development.
FEZF1 suppresses the transcription factor HES5, which helps regulate the differentiation of neural stem cells. FEZF1 helps divide the caudal forebrain into three distinct regions— , prethalamus, thalamus, and pretectum—during development: FEZF1 knockout mice lack a prethalamus and have a smaller thalamus.
A loss-of-function mutation in FEZF1 causes Kallmann syndrome.
As axons develop and migrate in the early embryo, FEZF1 enables the axons of olfactory neurons to connect to the central nervous system in a mouse model. During neural development, GnRH neurons migrate through one of these olfactory axon tracts, and the loss of FEZF1 function therefore leads to the loss of GnRH neurons in the brain, which is the hallmark of Kallmann syndrome.³⁵⁰

OMIM: FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1

FEZF1 is a candidate gene for ADHD.³⁵¹

1.143. ZNF763, Zinc Finger Protein 763¶

Other names: ZNF440L, Zinc Finger Protein 440-like, DNA-binding protein, ZNF

The ZNF763 protein is likely involved in transcriptional regulation via RNA polymerase II. ZNF763 appears to possess DNA-binding transcription factor activity and sequence-specific DNA-binding activity in the cis-regulatory region of RNA polymerase II. ZNF763 is thought to be localized in the nucleus.³⁵²

ZNF763 is a candidate gene for ADHD.²⁴²

1.134. ZNF615, Zinc Finger Protein 615¶

Alternative name: FLJ33710

The ZNF615 protein mediates DNA-binding transcription activator activity, as well as RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA-binding activity. ZNF615 is thought to be involved in the regulation of transcription by RNA polymerase II. ZNF615 is believed to be active in the cell nucleus.³⁵³

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.139. POLR1H, RNA Polymerase I Subunit H¶

Other names: Tctex-6, HTEX-6, HZR14, RPA12, A12, ZNRD1, DNA-Directed RNA Polymerase I Subunit RPA12, DNA-Directed RNA Polymerase I Subunit H, Zinc Ribbon Domain-Containing Protein 1, RNA Polymerase I Small Specific Subunit Rpa12, Transcription-Associated Zinc Ribbon Protein, Zinc Ribbon Domain-Containing Protein 1, TCTEX6, HTEX6, Rpa12, TEX6, ZR14, ZNRD1, ZINC RIBBON DOMAIN-CONTAINING PROTEIN 1, MOUSE, HOMOLOG OF; A12.2

The POLR1H protein is a DNA-dependent RNA polymerase I subunit. It may play a role in the regulation of cell proliferation. POLR1H catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. POLR1H is a component of RNA polymerase I.³⁵⁴ RNA polymerase (Pol) I produces ribosomal (r)RNA, an essential component of the cellular protein synthesis machinery that drives cell growth and underlies many fundamental cellular processes. Transcription by Pol I is subject to a series of complex regulatory mechanisms that influence rRNA production. Pol I-specific transcription factors direct Pol I to the rDNA promoter and contribute to multiple rounds of transcription initiation, promoter escape, elongation, and termination.³⁵⁵
POLR1H is associated with

• Cancer progression
• HIV
• Asthma
• Nasal polyps
• Aspirin intolerance
• Plantar warts

OMIM: ZNRD1, ZINC RIBBON DOMAIN-CONTAINING PROTEIN 1

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

Receptor activity¶

1.41. ARRB2, Arrestin Beta-2 Gene (Chromosome 17p13.2)¶

The protein β-arrestin (also known as β-arrestin 1 or arrestin 2) regulates the activity of G protein-coupled receptors (GPCRs). It causes

• reduced GPCR activation
• Endocytosis of the GPCR
• Connection between the GPCR signaling pathway and the Src signaling pathway
• Connection between the ERK signaling pathway and the Akt signaling pathway.

OMIM: Arrestin beta-2 gene, ARRB2

The ARRB2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.004.³

Neurotransmitter Storage¶

1.49. SYP, SYNAPTOPHYSIN (Chromosome Xp11.23)¶

Synaptophysin is found in synaptic vesicles of neurons in the brain, spinal cord, and retina, as well as in similar vesicles in the adrenal medulla and the motor end plate.
Little is known about the function of synaptophysin. It appears to form a channel in the membrane of nerve cells, which allows neurotransmitters to be taken up from the cytosol into the synaptic vesicles.

OMIM: SYNAPTOPHYSIN; SYP

In a 2006 study, the SYP gene was identified as a candidate gene for ADHD, with p = 0.045.³

Purine metabolism¶

1.115. NT5C2, 5’-Nucleotidase, Cytosolic II¶

Other names: CN-II, PNT5, SPG65, NT5B, GMP, Spastic Paraplegia 45 (Autosomal Recessive), Cytosolic Nucleoside Phosphotransferase 5’N, 5’-Nucleotidase (Purine), Cytosolic Type B, Cytosolic IMP/GMP-Specific 5’-Nucleotidase, Cytosolic Purine 5’-Nucleotidase

The NT5C2 protein is a hydrolase and a cytosolic 5’-nucleotidase with broad specificity. NT5C2 plays an important role in cellular purine metabolism. NT5C2 primarily acts on inosine-5’-monophosphate and other purine nucleotides. NT5C2 catalyzes the dephosphorylation of 6-hydroxypurine nucleoside-5’-monophosphates. NT5C2 possesses phosphotransferase activity, which allows it to transfer a phosphate group from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine, and guanosine.³⁵⁶

NT5C2 is associated with

• Chemotherapy resistance in relapsed acute T-cell lymphoblastic leukemia.
• Spastic paraplegia 45, autosomal recessive
• paraplegia

A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

Adhesion¶

1.288. PCDH7, Protocadherin 7¶

Other names: BH-Pcdh; PPP1R120; Protein Phosphatase 1, Regulatory Subunit 120; BH-Protocadherin (Brain-Heart); Brain-Heart Protocadherin; Protocadherin-7; BHPCDH

PCDH7 belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The PCDH7 protein is an integral membrane protein that appears to play a role in cell-cell recognition and adhesion and possesses an extracellular domain containing 7 cadherin repeats.³⁵⁷
PCDH7 expression increases during cocaine withdrawal.³⁵⁸
PCDH7 is associated with

• Astigmatism
• Epilepsy, juvenile myoclonic epilepsy

Related signaling pathways:

• Response to elevated cytosolic Ca2+ in platelets
• RHOC GTPase cycle
• Calcium ion binding

Paralog: PCDH1

This gene was identified as a candidate for ADHD in a large-scale GWAS.¹⁹³

1.53. SPATA13, SPERMATOGENESIS-ASSOCIATED PROTEIN 13 (Chromosome 13q12.12)¶

Other names: FLJ31208; Spermatogenesis Associated 13, ARHGEF29; ASEF2; APC-Stimulated Guanine Nucleotide Exchange Factor

The SPATA13 protein mediates guanylate nucleotide exchange factor (GEF) activity for the GTPases RHOA, RAC1, and CDC42, as well as identical protein-binding activity. SPATA13 is involved in cell migration, the formation of cell protrusions attached to the plasma membrane, the regulation of cell migration, as well as the establishment and disassembly of cell adhesions through a mechanism dependent on RAC1, PI3K, RHOA, and AKT1. SPATA13 increases both RAC1 and CDC42 activity but reduces the amount of active RHOA. SPATA13 is required for the upregulation of MMP9 via the JNK signaling pathway in colorectal tumor cells. SPATA13 is involved in tumor angiogenesis and may play a role in the formation of colorectal adenomas and tumor progression. SPATA13 is found in several cellular components, including filopodia, lamellipodia, and the ruffled border.³⁵⁹
SPATA13 is associated with

• Optic atrophy 3, autosomal dominant
• Dravet syndrome

OMIM: SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13

• SNP: rs17079773; Position: 23496384; Located in the intron of SPATA13 ¹⁶⁴
  Associated with inattention
  p: 4.71E-06

1.58. ITGAE, Integrin Subunit Alpha E (Chromosome 17p3.2)¶

Other names: HUMINAE; CD103; Integrin, Alpha E (Antigen CD103, Human Mucosal Lymphocyte Antigen 1; Alpha Polypeptide); Human Mucosal Lymphocyte Antigen 1, Alpha Polypeptide; Mucosal Lymphocyte 1 Antigen; Integrin Alpha-IEL; Integrin Alpha-E; HML-1 Antigen; Antigen CD103, Human Mucosal Lymphocyte Antigen 1; Alpha Polypeptide; Antigen CD103; CD103 Antigen; CD103

Integrins are heterodimeric integral membrane proteins consisting of an alpha chain and a beta chain. As transmembrane proteins, they span the cell membrane, where they are firmly anchored. They play an important role in cell signal transduction. They connect individual cells to one another and link cells to the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
ITGAE is a receptor for E-cadherin. It binds to integrin beta 7 (β7-ITGB7) to form the complete heterodimeric integrin molecule αEβ7. ITGAE mediates the adhesion of intraepithelial T lymphocytes to epithelial cell monolayers. ITGAE is an I-domain-containing alpha-integrin that undergoes posttranslational cleavage in the extracellular domain, resulting in disulfide-linked heavy and light chains. In combination with the beta-7 integrin, this protein forms the E-cadherin-binding integrin, known as the human mucosal lymphocyte-1 antigen. ITGAE is preferentially expressed in human intestinal intraepithelial lymphocytes (IELs) and, in addition to its role in adhesion, may also serve as an accessory molecule for IEL activation.³⁶⁰
ITGAE is affiliated with

• Enteropathy-associated T-cell lymphoma
• Mycosis fungoides

Related signal paths:

• Autophagy signaling pathway
• Dendritic Cell Developmental Lineage Pathway

Paralog: ITGA11.

OMIM: INTEGRIN, ALPHA-E

• SNP: rs220470 Position: 3611724; In the intron of ITGAE¹⁶⁴
  P: 1.34E−07
  A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

1.59. ITGA11, Integrin Subunit Alpha 11 (Chromosome 15q23)¶

Other names: HsT18964; Integrin Alpha-11; Integrin, Alpha 11

Integrins are heterodimeric integral membrane proteins consisting of an alpha chain and a beta chain. As transmembrane proteins, they span the cell membrane, where they are firmly anchored. They play an important role in cell signal transduction. They connect individual cells to one another and cells to the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
The ITGA11 protein is an alpha-integrin and contains an I-domain. ITGA11 is expressed in muscle tissue and dimerizes in vitro with beta-1 integrin, which appears to enable it to bind to collagen. The alpha-11/beta-1 integrin is a collagen receptor. Therefore, ITGA11 may be involved in the binding of muscle tissue to the extracellular matrix.³⁶¹
ITGA11 is associated with

• Oligodendroglioma of the brain
• Myasthenic syndrome, congenital, 19

Related signal paths:

• Autophagy signaling pathway
• PI3K-Akt signaling pathway
• Collagen binding
• Collagen receptor activity

Paralog: ITGA10.

OMIM: INTEGRIN, ALPHA-11

• Rs7164335 66502086 In the intron of ITGA11¹⁶⁴
  p: 1.30E−07
  A study identified this gene as one of the 51 most likely candidate genes for ADHD.¹⁰

Brain damage¶

1.287. SPAG16, Sperm-Associated Antigen 16¶

Other names: PF20; WDR29; Sperm-Associated Antigen 16 Protein; Pf20 Protein Homolog; DKFZp666P1710; FLJ22724; Sperm-Associated WD Repeat Protein; WD Repeat Domain 29

SPAG16 is essential for sperm flagellar function. SPAG16 encodes two major proteins associated with the axoneme of the sperm tail and the nucleus of postmeiotic germ cells, respectively. The axoneme is a microtubular framework consisting of cilia and flagella, organized by the basal body and surrounded by a plasma membrane. SPAG16 plays a role in the formation of motile cilia. SPAG16 is required for sperm flagellar function and may help recruit STK36 to the cilium or the apical surface of the cell to initiate the subsequent steps in the assembly of the central pairing apparatus of motile cilia.³⁶²
SPAG16 is associated with

• Pulmonary subvalvular stenosis (narrowing of the outflow tract from the right ventricle to the pulmonary artery)
• Cerebral Small Vessel Disease 2
  • Cerebral small-vessel disease
  • May lead to cognitive deficits in the areas of attention and executive function³⁶³

Related signaling pathway: Protein kinase binding.

SPAG16 was identified as an ADHD candidate gene in a large-scale GWAS.¹⁹³

Astrocytes¶

Astrocytes (astroglia) may be an important link between neuroinflammation and ADHD symptoms. Glial cells play a significant role in the immune response. In the three-part synapse, astrocytes are directly involved in maintaining the balance of the neurotransmitters dopamine and norepinephrine, functioning similarly to dopamine transporters by taking up dopamine and norepinephrine at the edge of the synaptic cleft.³⁶⁴

2.83. SNORC, Secondary Ossification Center-Associated Regulator of Chondrocyte Maturation¶

Other names: ASCL830; C2orf82; UNQ830; Secondary Ossification Center-Associated Regulator of Chondrocyte Maturation Protein; Small Novel Rich in Cartilage; Protein SNORC; Chromosome 2 Open Reading Frame 82; Uncharacterized Protein C2orf82

SNORC is a small, cartilage-specific transmembrane chondroitin sulfate proteoglycan.
SNORC is ³⁶⁵

• plays a role in cartilage development
• found in the extracellular space
• an integral part of the membrane
• active at the cell periphery.
• highly conserved in mammals
• has orthologs in all subgroups of vertebrates.

During development, expression is highest in the proliferating and prehypertrophic zones. In adult articular cartilage, expression was restricted to the noncalcified zone. Snorc is co-expressed with Sox9, Acan, and Col2a1 and is upregulated by BMP-2.³⁶⁶

SNORC is found

• in the collagen-rich extracellular matrix
• in the cytoplasm

In ADHD, SNORC expression appears to be reduced and methylation appears to be increased.¹⁴³
SNORC in astrocytes is a candidate gene for late-diagnosed ADHD.³⁶⁷
SNORC has been identified as a candidate for ADHD.²⁹¹.

1.152. ALS2CR8, CARF¶

Other names: Calcium-Responsive Transcription Factor, Calcium-Response Factor, NYD-SP24, ALS2CR8, Amyotrophic Lateral Sclerosis 2 Chromosomal Region Candidate Gene 8 Protein, Amyotrophic Lateral Sclerosis 2 (Juvenile) Chromosome Region, Candidate 8, Calcium-Responsive Transcription Factor, Testis Development Protein NYD-SP24, FLJ21579, CaRF

The ALS2CR8 protein is a DNA-binding transcription factor and mediates DNA-binding activity. ALS2CR8 is involved in the cellular response to potassium ions and in the positive regulation of transcription from the RNA polymerase II promoter in response to calcium ions. ALS2CR8 binds to the consensus calcium response element CaRE1, with the sequence 5’-CTATTTCGAG-3’. ALS2CR8 is thought to be localized in the granular fraction and to be active in the nucleus. CARF is associated with:³⁶⁸

• Amyotrophic Lateral Sclerosis 2, juvenile
• Moyamoya disease 1
  • Moyamoya causes ADHD symptoms.

ALS2CR8 is a candidate gene for ADHD.²⁴²
CARF in astrocytes is a candidate gene for childhood ADHD.³⁶⁷

1.365. GFOD1, glucose-fructose oxidoreductase domain 1¶

Rats with ADHD exhibited increased GFOD1 expression in the PFC and cerebellum, supported by neuronal damage and increased expression of glial fibrillary acidic protein (GFAP) in astrocytes. Overexpression of GFOD1 in astrocytes led to a comparable upregulation of this signaling pathway.
ADHD rats, like astrocytes with overexpressed GFOD1, showed:³⁶⁹

• increases reactive oxygen species (ROS)
• Malondialdehyde (MDA) levels increase
• Reduced superoxide dismutase (SOD) activity

Methylphenidate did not affect GFOD1 expression, but it did affect the levels of oxidative stress mediated by the NF-κB p65/NOX2 signaling pathway.
GFOD1 appears to contribute to increased oxidative stress in the PFC, cerebellum, and astrocytes by upregulating the NF-κB p65/NOX2/oxidative stress axis.