1. Genes as genetic candidates in ADHD with plausible pathway to ADHD.

This article and the one that follows rank more than 300 ADHD gene candidates according to their possible pathway of action on ADHD. This article is arranged according to the best known and most distinct mechanisms of action, starting with dopamine, norepinephrine, and other neurotransmitters. In this ordering system, the gene candidates have each been classified under the one of their (and known) mechanisms of action that is most closely associated with ADHD.
However, the degree of influence of the different mechanisms of individual genes on ADHD is often unknown, which clearly limits the resilience of the classification. For example, we classified genes that showed a link to dopamine there as long as it was not positively apparent that another pathway of the gene had a greater influence in relation to ADHD. For example, a dopaminergic pathway was sufficient for us to classify it under dopamine, even though other pathways are known to correlate with ADHD development as well. This is, by its nature, very truncating. We hope to gradually add more information that will improve the classification of the genes,

So far, the review primarily serves to guide which mechanisms of action are served by quite a few ADHD candidate genes, which provides some indication that the pathway is related to the development of ADHD.
Meanwhile, we know of no other publication that so comprehensively attempts to rank the ADHD gene candidates by mechanism of action on ADHD: We therefore hope that, despite its limitations, this account may give an interesting impression of the likely and possible pathways of ADHD development.

Gene candidates for which we have not yet been able to determine how they may influence the development of ADHD are collected in the following article.

One study found 560 genes and 6 miRNA that showed aberrant expression in ADHD compared to non-affected individuals.¹ Changes in gene expression cause a deviating activity of the gene and thus of the effects mediated by it (e.g. activity of a receptor, transporter, protein). Other studies found many other genes that could be considered, so that a four-digit number of candidate genes can currently be assumed.
An interesting study of 1033 ADHD sufferers against 950 unaffected individuals reached a result that achieved diagnostically relevant values of accuracy (0.9018), AUC (0.9570), sensitivity (0.8980), and specificity (0.9055) by considering the combined effect of multiple variants with insignificant P values and analyzing them using DeepLearning (“AI”). The study found 96 candidate genes, of which only 14 genes had previously been reported in ADHD-related studies.²

The Chinese ADHDgene database lists genes relevant for ADHD.³ However, it does not appear to have been updated since 2014.

Some of the genes listed below cause rare (orphan) diseases when a gene defect is present. For example, the SYNE1 gene (one of the 560 genes from the study by Nuzziello et al) causes SYNE1 ataxia in 20 out of 100,000 people, so it has a prevalence of 0.02%.⁴ The following thought experiment may give an idea of the contribution of individual genes to ADHD: If all of the 560 genes named as candidate genes for ADHD were to cause such a rare orphan disorder (each of which would be associated with ADHD symptoms), and if each gene alteration occurred only alone, the sum of these 560 genes would already result in a prevalence of 11.2%, which would correspond to or exceed the prevalence of ADHD.

Gene Databases:

• GeneCards.org
• omim.org
• Uniprot.org/

• 1. Genes that appear to be involved in the development of ADHD (candidate genes)
• 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
  • 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 effect
    • 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
  • 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, Mannosidase Alpha Class 2A Member 2
  • 2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A
    • Dopamine metabolization
      • 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
• Norepinephrine
  • Noradrenaline synthesis
    • 1.7. DBH, dopamine beta-hydroxylase (chromosome 9q34.2; Taql A)
  • Norepinephrine action
    • 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 degradation
    • Norepinephrine reuptake
      • 1.18. NET, noradrenaline transporter gene (chromosome 16q12.2)
• 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)
  • Serotonin effect
    • 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 degradation
    • Serotonin Reuptake
      • 1.15. SLC6A4, serotonin transporter gene, 5-HTT gene (chromosome 17q11.2)(x)
    • Serotonin Metablization
      • 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-alpha3 (chromosome Xq28)
  • 1.23. GABA receptor-beta-3 (chromosome 15q11.2-q.12)
  • 1.35. CDH13, Cadherin13 (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 degradation
  • 1.40. SLC5A7, CHT1, CHOLINE TRANSPORTER
  • 1.237. SLC44A1, Solute Carrier Family 44 Member 1
• Glutamate
  • 1.39. GRM1, glutamate receptor metabotropic 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, glutamate receptor metabotropic 5 (chromosome 11q14..2 - 14.3) (33, p. 55)
  • 1.38. GRM7, glutamate receptor metabotropic 7 (chromosome 3p26.1)
  • 1.43. SLC9A9, Solute Carrier Family 9 Member A9 (Chromosome 3q24)
• Cannabinoids
  • 1.37. CNR1, cannaboid receptor 1 (chromosome 6q14-q15)
• Traceamine
  • 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
• Brain development
  • 1.33. NDE1, Nuclear distribution gene E homologue 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
• Growth factors, neurogenesis
  • 1.25. NTF3, neurotrophin 3 (chromosome 12p13.31)
  • 1.71. NTF4, NEUROTROPHIN 4 (chromosome 19q13.33)
  • 1.26. BDNF, Brain-derived-neurothropic-factor (chromosome11p14.1) (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 OF, 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)
• 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 stress consequences
  • 1.108. NCL, nucleolin
• Broadly effective 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
    • 1.93. TAF1, TAF1 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 250-KD
    • 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)
• Cerebral damage
  • 1.287. SPAG16, Sperm Associated Antigen 16

1. Genes that appear to be involved in the development of ADHD (candidate genes)¶

Dopamine¶

Dopamine synthesis¶

1.8. DDC, AADC, aromatic-L-amino acid decarboxylase (chromosome 9q34.2)¶

Other names: DOPA-dercaboxylase

OMIM: DOPA decaboxylase gene, DDC

DDC is a candidate gene for ADHD.⁵

The DDC gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.039.⁶

In children with hyperactivity (but not in adults), one study found decreased striatal and prefrontal dopa decarboxylase activity.⁷

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 protein TH catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa), the rate-limiting step in the biosynthesis of cathecolamines, dopamine, norepinephrine, and epinephrine. TH uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to 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 show no catalytic activity.⁸
TH is associated with

• Segawa syndrome, autosomal recessive
• Dystonia

Related Signal Paths:

• dopaminergic neurogenesis
• Metabolism of amine-based hormones
• Enzyme binding
• Oxygen binding

Paralog: PAH

Tyrosine hydroxylase is a candidate gene for ADHD.⁵

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 to the much 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 an alteration in striatal dopamine synthesis capacity.⁹

One study found AS3MT to be one of the 51 most likely gene candidates for ADHD.¹⁰

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, 25kDa; Synaptosomal-Associated Protein 25; SUP; Synaptosomal-Associated 25 KDa Protein; Synaptosome Associated Protein 25kDa; 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 at the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For the t-SNAREs on the plasma membrane, the protein syntaxin provides 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 odulates the gating properties of the voltage-gated potassium channel KCNB1 with delayed rectification in pancreatic beta cells.¹¹
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.⁵¹² SNAP25 was identified as a candidate gene for ADHD in a 2006 study with p = 0.035.⁶

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 serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. 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 could regulate membrane interactions during 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 headgroup 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 melanocyte dendrite formation. SYT1 can bind to at least three other proteins in a Ca(2+)-independent manner:¹³

• Neurexin
• Syntaxin
• AP2

Whereas Syt7 (synaptotagmin7), a high-affinity Ca2+ sensor, underlies phasic somatodendritic dopamine release and its Ca2+ sensitivity in substantia nigra pars compacta, SYT1, as a Ca2+ sensor, underlies axonal dopamine release and plays a role in tonic but not phasic somatodendritic dopamine release. However, SYT1 may facilitate phasic dopamine release when SYT7 is deactivated. SYT1 and SYT7 function as Ca2+ sensors that support different aspects of somatodendritic dopamine release.¹⁴

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 thought to correlate with common ADHD symptoms.¹⁵

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 has unique mechanochemical properties used for membrane tubulation and disruption, and 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, resulting in stimulation of GTPase activity.¹⁶
Connected signal paths:

• Integrin Path
• Development of the nervous system.

Mutations in DNM1 are associated with

• Autism¹⁷
• epileptic encephalopathy¹⁸
  • infantile spasms with onset between 2 and 13 months of age
  • later development of Lennox-Gastaut syndrome
  • severe to profound mental retardation
  • pronounced hypotension
  • missing language.

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

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

Dopamine effect¶

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

OMIM: Dopamine receptor D1 gene, DRD1

DRD1 is a candidate gene for ADHD.⁵

The DRD1 receptor is closely related to the DRD5 receptor, but is found in other brain regions, namely in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex - i.e. in brain regions where DRD1 receptors are hardly found.¹⁹

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

OMIM: Dopamine receptor D2 gene, DRD2
DRD2 is a candidate gene for ADHD.⁵

The A allele has been associated with lower receptor density in the striatum in several studies. This means that existing dopamine can be taken up to a lesser extent, which has the same effect as a reduced dopamine level.²⁰
The DRD2-A1 allele is thought to correlate with impulsivity, compulsivity, and addiction²¹

One study found significantly increased ADHD and ASD risk overlap in correlation with the DRD2-12 (rs7131465) gene polymorphism.²²

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

OMIM: Dopamine receptor D3 gene, DRD3
DRD3 is a candidate gene for ADHD.⁵

In mice, an effect of the D3 receptor on increased motor activity (hyperactivity) and rearing behavior (“rearing behavior”) was found. Binding of the D3 receptor prevents addictive behavior (craving).

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

OMIM: Dopamine receptor D4 gene, DRD4

DRD4 is a candidate gene for ADHD.^2312524
DRD4 was identified as a candidate gene for ADHD in a 2006 study with p = 0.055.⁶
The DRD4-7R variant increases the risk of ADHD by 50% (odds ratio 1.5).²⁵
The 7-repeat allele encodes the dopamine receptor D4 in such a way that it requires 3 times the amount of dopamine to respond. ²⁶²⁷ This acts like an apparent decreased dopamine level in the striatum, which correlates with motivational problems and impulsivity²⁸
In other words, DRD4-7R causes reduced postsynaptic inhibition.²⁹³⁰
A recent report suggests that DRD4-7R is not simply more insensitive to dopamine, but rather interacts with other dopamine receptors. Moreover, DRD4, like all D2-type receptors (D2, D3, and D4), is also thought to respond to norepinephrine as an agonist.³¹

DRD4-7R increases the reactivity of the ventral striatum as a result.
Thus, DRD4-7R does not per se cause lower levels of dopamine in the striatum, but reduces inhibition of the striatum by only responding inhibitively to higher levels of dopamine.
Surprisingly, however, DRD4-7R has an additional inhibitory effect on a methamphetamine-triggered increase in dopamine and glutamate in the striatum. A methamphetamine-triggered increase in dopamine and glutamate was reduced in mice carrying the DRD4-7R gene.³² In contrast, cocaine did not show reduced dopamine or glutamate increases in DRD4-7R. The dopamine increase on cocaine was marked in all DRD4 variants, whereas the glutamate increase was rather small.
Striatal glutamate stimulates dopamine increase in the striatum.³²
Adenosine modulates striatal DA release by stimulating glutamate release at adenosine receptors in the striatum, which increases dopamine levels.³³
DRD4-7R causes decreased function and connectivity of brain regions involved in inhibitory control during impulse control task execution, particularly the right inferior frontal gyrus cortex.³²³⁴³⁵
Flattened 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 reactivity to non-reward or aversive stimuli.³⁶
This increases “interest” in irrelevant stimuli and decreases inhibition of irrelevant responses, as evidenced by distractibility and action and decision impulsivity in ADHD.³² This contradicts representations that DRD4-7R should be associated with ADHD-I subtype.

We hypothesize that DRD4-7R is linked to increased impulsivity, which is more typical of the ADHD-HI subtype.
DRD4-7R is associated with Novelty Seeking.⁴² Novelty Seeking correlates with high impulsivity.

A cohort study found that DRD4-7R correlated with high levels of hyperactivity/impulsivity quite generally.⁴³

DRD4-7R causes less formation of gyri and sulci (gyrification) in the PFC of ADHD sufferers.⁴⁴

DRD4-7R is only about 40,000 to 50,000 years old and has since spread far more rapidly than would be expected from random gene transmission. This suggests that DRD4-7R is an extremely successful gene.³⁰⁴⁵

DRD4-4R and DRD4-7R appear to strongly and differentially affect the functionality of the D2-short receptor variant.⁴⁶

A review on the epigenetic causation of ADHD points to the relevance of DRD4.⁴⁷

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.¹²⁵

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 where DRD1 receptors are scarce.¹⁹
DRD5 is widely distributed in the brain and is significantly more affine for dopamine than the D1 receptor. The DRD5-148-bp allele is associated with ADHD in 18.5 kb at the end of the 5′-flank.⁴⁸
DRD5 appears to moderate the hypothalamus and parts of motor control.⁴⁹

1.234. ADORA2A, ADENOSINE A2A RECEPTOR¶

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

OMIM: ADENOSINE A2A RECEPTOR; ADORA2A

The protein ADORA2 is the adenosine A2a receptor. ADORA2 is a member of the guanine nucleotide-binding protein (G-protein)-coupled receptor (GPCR) superfamily, which is divided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular stimuli and activate intracellular signal transduction pathways. ADORA2 uses adenosine as a preferred endogenous agonist and interacts preferentially with the G(s) and G(olf) family of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. A2A receptors show high expression in spleen, thymus, leukocytes, platelets and olfactory bulb.⁵⁰
ADORA2 is associated with

• Acute encephalopathy with biphasic seizures and late reduced diffusion
• Basal ganglia disease
• Inflammatory diseases
• neurodegenerative disorders

Paralog: ADORA2B

One study reports a possible significant association between the A2AAR gene polymorphism rs35320474 and ADHD.⁵¹

Adenosine is very closely linked to the action of dopamine. Adenosine A2A receptors and dopamine receptors form receptor heterodimers. Adenosine inhibits dopamine via the A2A receptor. For more information 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 by hydrolysis of phosphoric acid monoesters. They counteract the action of kinases and phosphorylases, are involved in signal transduction and in the inhibition of cell growth and division.
PPP2R2B modulates substrate selectivity and catalytic activity as well as the localization of the catalytic enzyme in a specific subcellular compartment. Isoform 2 is required for the promotion of proapoptotic activity and regulates neuronal survival by balancing mitochondrial fission and fusion.⁵²

PPP2R2B is associated with

• autosomal dominant spinocerebellar ataxia 12 (SCA12; degeneration of cerebellum and sometimes brainstem and spinal cord; poor coordination of speech and body movements)
• autosomal dominant cerebellar ataxia

PPP2R2B and dopamine:
The signaling action 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. Moreover, 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-gated inwardly rectifying potassium channels (e.g., GIRK2/KCNJ6). In addition, DRD2 modulates neuronal function by acting on G-protein-independent mechanisms. Upon activation, dopamine receptors are phosphorylated by G-protein 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 cell signaling functions. In the case of DRD2, recruitment of ARBB2 leads to the formation of a protein complex that promotes inactivation of Akt family protein kinases (AKT1, AKT2, AKT3) by protein phosphatase 2 holoenzymes (i.e., PPP2R2B, PPP2CA, PPP2CB). Inactivation of AKT kinases downstream of DRD2 triggers inhibition of glycogen kinase 3 family proteins (GSK3A, GSK3B), thereby increasing their activity.⁵³

A SNP associated with PPP2R2B expression (rs959627) appears to predict prefrontal activity during the N-back working memory task.
The allele rs959627T correlated with:⁵⁴

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

One study found PPP2R2B to be one of the 51 most likely gene candidates for ADHD.¹⁰ Another study found PPP2R2B rs9325032 to be the gene most strongly associated with ADHD⁵⁵

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 major role in dopamine reuptake, is found primarily in the striatum⁵⁶ and is much more abundant there than in the PFC.

The DAT gene is often cited as an ADHD candidate gene.^2312524 The DAT1 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.005.⁶
In particular, the DAT1 variant 10/10 is associated with increased ADHD symptoms⁵⁷
A particular DAT1 variant is said to be primarily associated with the ADHD-HI subtype.³⁷ The binding of DAT, which is largely determined by the DAT1 gene, is associated with motor hyperactivity, but not with inattention.²³ In the ADHD-HI subtype (with hyperactivity), the striatum is primarily affected. The caudate nucleus is conspicuously reduced in size.⁵⁸
A certain DAT1 gene variant causes an excessive number of dopamine transporters. An excessive number of dopamine transporters causes the dopamine released presynaptically (by the sending neuron) to be taken up again by the excess DAT like a vacuum cleaner from the presynapse (the sending neuron) before it could be taken up postsynaptically (by the receiving neuron). The correctly released amount of dopamine therefore does not arrive at the postsynaptic dopamine receptors, which is why they do not receive the required amount of decision information (which would only be triggered if a sufficient number of the receptors had received dopamine).³⁸⁵⁹
The polymorphisms of the DAT gene in question occur significantly more frequently in families of ADHD sufferers (n = 329). A combination of 3 specific polymorphisms was associated with a 2.5-fold frequency of ADHD.⁶⁰
Certain DAT1 variants cause a predisposition to lower birth weight and ADHD susceptibility.⁶¹
DAT Val559, unlike the DAT Ala559 variant, is thought to be associated with increased dopamine transport, which may be relevant in ADHD, autism, and bipolar disorder.⁶²
The DAT1 rs27048 (C)rs429699 (T) haplotype was associated with altered functional connectivity of the left dorsal caudate nucleus in visual memory performance of adolescents with ADHD in one study.⁶³

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, NORADRENALINE), MEMBER 2; SLC6A2, NET

SLC6A2 is a candidate gene for ADHD.⁵⁶⁴

The NET gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.012.⁶

Children with ADHD with the SLC6A2 rs36011 (T) / rs1566652 (G) haplotype showed abnormalities in intrinsic brain activity of the sensorimotor and dorsal attention networks that correlated with impairments in visual memory and visual attention.⁶⁵

NET1-rs3785143 is reported to be associated with increased emptional lability in ADHD.⁶⁶

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

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

Pore-forming alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents. Mediates influx of calcium ions into the cytoplasm, thereby triggering calcium release from the sarcoplasm. Important for excitation-contraction coupling in the heart. Required for normal cardiac development and normal cardiac rhythm regulation. Required for normal contraction of smooth muscle cells in blood vessels and intestine. Essential for normal blood pressure regulation through its role in contraction of arterial smooth muscle cells.⁶⁷
Acts as a receptor for influenza viruses. CACNA1C may be relevant for enabling virus entry when sialylated and expressed on lung tissue
CACNA1C is associated with clinical diagnoses of:⁶⁸

• 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 nucleus accumbens. Decreased CACNA1C levels attenuate mesolimbic dopamine system function: in mice with CACNA1C haploinsufficiency, subsecond frequency dopamine release was insensitive to DAT inhibition. Constitutive CACNA1C haploinsufficiency produced reduced hypermotor activity after acute administration of DAT-specific stimulants. 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. Because the identified single nucleotide polymorphisms are found in an intronic (nonprotein-coding, “in intron”) region of CACNA1C, genetic risk influence is likely to occur via altered CACNA1C levels in specific brain regions.⁶⁸ Hyperlmotor activity triggered by high doses of d-amphetamine is attenuated in mice lacking one copy of CACNA1C .⁶⁹

One study found this gene to be one of the 51 most likely gene candidates 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 calcium channel function by increasing peak calcium current, shifting the voltage dependence of activation and inactivation, modulating G-protein inhibition, and controlling membrane targeting of the alpha-1 subunit.⁷⁰
CACNB2 is associated with:⁷¹⁷²

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

Related Signal Paths:

• sensory processing of sound
• CREB signal path

Stimulation of L-type calcium channels increases tyrosine hydroxylase And dopamine in ventral midbrain cells.⁷³ In addition, there are quite a few other evidences that L-type calcium channels affect dopamine balance.^74757677

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰
Mutations in the CACNB2 gene, in addition to ADHD, have been further associated with:⁷⁸

1.105. MAN2A2, Mannosidase Alpha 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 protein MAN2A2 enables 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 integrative component of the membrane and 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-glucoside bonds and (1,6)-beta-glucoside bonds, releasing alpha-glucose and beta-glucose.⁷⁹ MAN2A2 - like MAN2A2 - is expressed at relatively high levels, presumably because they are required for complex N-glycans⁸⁰
MAN2A2 is associated with

• abdominal obesity - metabolic syndrome Quantitative Trait Locus 2
• Schizophrenia (equivocal)⁸⁰

MAN2A1-KO mice show deficiency of N-glycans on erythroid cells, anemia, and late-onset autoimmune disease similar to systemic lupus erythematosus, but otherwise no disorders.
MAN2A2-KO mice show male infertility without other disorders.
Deletion of either MAN2A1 or MAN2A2 alone results in relatively mild and organ-specific phenotypes.
In contrast, deletion of MAN2A1 and MAN2A2 together triggers perinatal lethality and complete deficiency of complex N-glycans⁸⁰

The dopamine D2 receptor is subject to N-glycosylation. N-glycans at the N-terminus of the D2 receptor suppress internalization of the receptor into the cytosol because they are required for interaction with caveolin-1, a negative regulator of endocytosis. N-glycans are involved in the desensitization and expression of the dopamine D3 receptor on the cell surface and in its clathrin-dependent internalization from the plasma membrane.⁸¹
Glycosylation of DAT correlates with susceptibility of midbrain dopaminergic cells in PD.⁸²
The DAT is a glycoprotein with three N-glycosylation sites in the second extracellular loop (Horn, 1990; Giros and Caron, 1993).
Blockade of N-glycosylation (of DAT) decreased DAT at the surface as well as intracellularly. Although partially or nonglycosylated DAT was slightly less represented at the surface, no evidence was found for preferential exclusion of such material from the plasma membrane, suggesting that glycosylation is not essential for DAT expression. Nonglycosylated DAT were less stable at the surface, as evidenced by markedly enhanced endocytosis. Nonglycosylated DAT did not transport dopamine as efficiently as wild-type DAT. Blockade of N-glycosylation enhanced the efficacy of cocaine-like drugs in inhibiting dopamine uptake. Non-glycosylated DAT at the cell surface showed significantly reduced catalytic activity and altered sensitivity to reuptake inhibitors compared with wild type.⁸³

One study found MAN2A2 to be one of the 51 most likely gene candidates for ADHD.¹⁰

2.104. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

Witere names: STT3-A, TMC, Integral Membrane Protein 1, ITM1, Dolichyl-Diphosphooligosaccharide Protein Glycosyltransferase Subunit STT3A, STT3A, Catalytic Subunit Of The Oligosaccharyltransferase Complex, Dolichyl-Diphosphooligosaccharide Protein Glycotransferase, Oligosaccharyl Transferase Subunit STT3A, Transmembrane Protein TMC

The protein STT3A is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex that transfers glycan chains to asparagine residues of target proteins in the endoplasmic reticulum. It is associated with CFTR activation by S-nitrosoglutathione (normal and CF) and translation of structural proteins.
STT3A is associated with

• congenital disorder of glycosylation, type Iw, autosomal recessive
• congenital disorder of glycosylation, type Iw, autosomal dominant

In light of the influence of STT3A on N-glycolysis, we assume a comparable pathway of action on the dopaminergic system as in 1,105. MAN2A2.

One study found STT3A to be one of the 51 most likely gene candidates for ADHD.¹⁰

Dopamine metabolization¶

1.10. MAOA, monoamine oxidase A gene (chromosome Xp11.3) (x)¶

OMIM: Monoamine oxidase A gene, MAOA

MAO-A is a candidate gene for ADHD.⁵

The MAO-A gene controls the formation of the enzyme monoamine oxidase-A. The MAO-A gene was identified as a candidate gene for ADHD with p = 0.02 in a 2006 study.⁶
A certain variant of the MAO-A gene doubles the risk of aggression and antisocial behavior if those affected were themselves exposed to violence (or let’s say more generally: intense stress) in 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, although often co-occurring with ADHD-HI (not ADHD-I), and not a part of ADHD. So does Steinhausen regarding social behavior disorders,⁸⁴ which is the most common comorbidity. However, Steinhausen describes the comorbidity of social behavior disorders as a subtype of ADHD, which we disagree with because of the delineability of the remaining genetic basis. Further arguing for 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 at the (inhibitory*) D2 receptor, whereas ADHD tends to be thought to have too little receptor affinity (see above).

1.11. MAOB, monoamine oxidase B gene (chromosome Xp11.4-p11.3)¶

MAO-B is a candidate gene for ADHD.⁵

In contrast to MAO-A inhibitors, MAO-B inhibitors have been shown to be ineffective in ADHD.⁸⁵

1.12. COMT, catechol-O-methyltransferase (chromosome 22q11.21)¶

OMIM: Catechol-O-methyltransferase; COMT

COMT is a candidate gene for ADHD.⁵

1.12.1. COMT Val158Val¶

The COMT gene variant Val158Val causes increased degradation of dopamine and norepinephrine, leading to dopamine deficiency in the PFC, which in turn, however, may cause increased dopaminergic activity in the mesolimbic system.^{8687 88 89} .⁹⁰

1.12.2. COMT Met158Met¶

The COMT Met158 Met variant correlates with antisocial behavior in ADHD.⁹¹

This could explain why this gene variant is only observed in ADHD with comorbid antisocial behavior, but to our knowledge not in ADHD in general. In addition, this gene variant is associated with borderline and (via increased dopaminergic activity of the mesolimbic system) the positive symptoms of schizophrenia.
This gene variant directly impairs working memory, which in turn indirectly controls delay aversion and directly controls executive functions and attentional control, and together with the latter, the processing of auditory stimuli, which are prerequisites for language processing. On the question of whether this COMT gene variant correlates with ADHD, there are more contradictory than confirmatory studies, which, however, did not take working memory into account.⁹²
This gene variant is further relevant in antisocial behavior disorder associated with ADHD, but not in ADHD without antisocial behavior disorder.⁸⁷ However, in our understanding, antisocial behavior disorder is a comorbid disorder and not part of ADHD.

1.12.3. COMT Val108/158 Met¶

The COMT Val108/158 Met polymorphism reduces the activity of the enzyme in degrading dopamine to one quarter. This variant correlates with a more focused and efficient cerebrovascular response in working memory tasks. ⁹³
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 causes the breakdown of dopamine by sulfation. More about this under Sulfation by sulfotransferases In the article Dopamine degradation.

The STS gene is an ADHD gene candidate.⁹⁴⁹⁵

Dopamine regulation¶

1.31. DRD1IP, calcylon (chromosome 10q26) (x)¶

Other names: DOPAMINE RECEPTOR D1-INTERACTING PROTEIN

Calcylone is involved in the regulation of the D1 receptor.⁹⁶

OMIM: Calcyon (CALY) gene / DOPAMINE RECEPTOR D1-INTERACTING PROTEIN; DRD1IP gene

CALY / DRD1IP is a candidate gene for ADHD.⁵

1.78. MTHFR, 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE¶

The enzyme methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylene-FH4 with the help of NAD(P)H to 5-methyl-FH4. Since this produces the methylating agent 5-methyl-FH4, MTHFR is indispensable in many metabolic pathways, including the degradation of harmful homocysteine to methionine, and in bacterial methane formation.
Humans express MTHFR in many tissue types, from where the protein is released into the blood. Variants and mutations of the MTHFR gene can lead to decreased, and less commonly increased, MTHFR synthesis and efficacy. MTHFR deficiency can

• be the cause of neural tube malformations such as spina bifida in the newborn in pregnant women
• Trigger homocystinuria
• Increase risk of stroke
• Increase colorectal cancer risk.

Homocysteine decreases dopamine levels in the striatum.⁹⁷

OMIM: MTHFR (5,10-METHYLENETETRAHYDROFOLATE REDUCTASE)

The 1298A > C polymorphism of the MTHFR gene has been associated with an increased risk of ADHD, but not the MTHFR 677 C > T polymorphism.⁹⁸

The MTHFR 1298A > C polymorphism is associated with increased homocysteine levels, probably due to decreased degradation of homocysteine by this polymorphism.⁹⁹

ADHD correlates with elevated homocysteine levels (and decreased vitamin B12 levels).¹⁰⁰¹⁰¹
B12 deficiency can increase homopcysteine levels.¹⁰²

1.81. ARTN, Artemin; 1p34.1¶

ARTN (artemin, enovin, neublastin) is a neurotrophic factor from the glial cell line-derived neurotrophic factor family of ligands, a group of ligands within the TGF-beta superfamily of signaling molecules. ARTN promotes survival of a number of peripheral neuron populations and at least one population of CNS dopaminergic neurons. ARTN frequently expresses in the vicinity of these neurons. ARTN is a ligand for the RET receptor and utilizes GFR-alpha 3 as a coreceptor. ARTN plays a role in axonal development.
ARTN is involved in the structural development and plasticity of several types of neurons, including the dopaminergic neurons of the ventral mesencephalon. ARTN plays an important role in the migration, proliferation and differentiation of sympathetic neurons during development.

OMIM: ARTN, Artemin; 1p34.1

Increased expression and decreased methylation in ADHD.¹⁰³
Candidate gene in a GWAS investigation.¹⁰⁴

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 G protein-coupled receptor signaling (especially Gq/11 as well as somewhat weaker G12/13), phospholipase C-activating G protein-coupled receptor signaling and signal transduction. GPR139 may play a role in motor activity, food intake, alcohol dependence and hyperalgesia and phenylketonuria (PKU)
Endogenous agonists are probably the aromatic amino acids L-Trp and L-Phe and ACTH/α-MSH-related peptides. GPR139 appears to increase cAMP and cause an ERK phosphorylation reaction.
GPR139 appears to form receptor heterodimers with the dopamine D2 receptor and moderate D2 activation.¹⁰⁵

The GPR139 receptor is expressed almost exclusively in the brain, particularly in the ventrolateral region of the putamen caudatus, the nucleus habenularis, the zona incerta, and the nucleus mammillaris medialis,¹⁰⁶ according to another source in the striatum, thalamus, hypothalamus, pituitary, and habenula of the CNS.¹⁰⁵

GPR139 appears to be associated with:¹⁰⁵

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

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

1.279. FOXP2¶

Substitution of two amino acids (T303N, N325S) in the transcription factor FOXP2 in mice showed decreased dopamine levels in:¹⁰⁷

• Nucleus accumbens
• Frontal cortex
• Cerebellum
• Putamen caudatus
• Globus pallidus

A connection with ADHD has not been proven so far, but is expected by us.

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; Only 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 dopamine signaling and critically influences the differentiation, maturation, and maintenance of dopaminergic neurons in the midbrain. NURR1 is found in several regions of the central nervous system, including the cortex, hippocampus, brainstem, spinal cord, and olfactory bulb¹⁰⁸
Mice in which NURR1 was deactivated (NURR1-KO mice) developed hyperactivity and impulsivity, but not the other ADHD symptoms such as anxiety, physical coordination problems, altered social behavior, or memory problems. Neither tyrosine hydroxylase (which limits catecholamine synthesis) nor dopamine levels were altered by NURR1 blockade. Hyperactivity caused by NURR1 deactivation could be corrected by methylphenidate.¹⁰⁹ Nurr1-KO mice (Nurr1-/-) are unable to develop midbrain dopaminergic neurons and die shortly after birth. These mice show impaired motor function and substantial loss of dopaminergic neurons in the SNpc and VTA. Expression of NURR1 in midbrain dopaminergic neurons decreases with age, coinciding with increased morbidity of PD¹⁰⁸
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. In addition, NURR1 activates transcription of the TH gene, thus exerting considerable influence on dopamine synthesis.
NURR1 mutations and polymorphisms causing either decreased expression or dysfunction have been associated with familial and sporadic PD¹⁰⁸

The protein NR4A2 (NURR1) is a member of the steroid thyroid hormone retinoid receptor superfamily. NR4A2 is a transcriptional regulator important for the differentiation and maintenance of meso-diencephalic 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. ¹¹⁰
NR4A2 is associated with

• Intellectual developmental disorder with language impairment
• early-onset dopa-reactive 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 protein CSMD1 is thought to be involved in learning and memory, branching of mammary glands during pregnancy, and development of reproductive organs. CSMD1 is probably an integral component of the membrane. CSMD1 is a potential suppressor of squamous cell carcinoma.¹¹¹

CSMD1 is associated with

• Autism
• Schizophrenia¹¹²
• Anorexia nervosa¹¹³

CSMD1 belongs to the same signaling pathway as CREB3, PTPRD and GAB1, and is involved in neuron differentiation and the **dopamine pathway **.¹¹³
CSMD1 plays a role in the ratio of dopamine and serotonin metabolites In CSF.¹¹⁴
CSMD1:c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) were identified as candidate genes for Parkinson’s disease, which is also caused by dopamine disorders.¹¹⁵

One study found CSMD1 to be one of 51 most likely candidate genes for ADHD.¹⁰ One study found CSMD1 (variant rs6559123) to be one of the 20 most likely among 96 ADHD candidate genes.²

Potassium channels influence dopamine¶

The function of potassium channels may influence dopaminergic tone. Therefore, potassium channels may be involved in the development of ADHD, but also schizophrenia and ASD.^116117118119

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 greater potassium flux into the cell than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is increased, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blocking of the outward current by internal magnesium. These proteins modulate many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells, by stimulating G protein-coupled receptors. The potassium channel KCNJ6 may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters acting through 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-severe intellectual disability syndrome)
  • rare disease (less than 1 / 1,000,000)
  • severe developmental delay
  • Facial dysmorphism
  • mental disability
• Epilepsy
• ADHD

Related Signal Paths:

• Potassium channels
• Progeria-associated lipodystrophy
• Inward potassium channel activity
• Activity of the G protein-activated inwardly rectifying 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 affected EEG in the N-back task in ADHD.
KCNJ6 rs6517442 affected ventral striatum activation during reward anticipation.¹¹⁶

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 of the S9B family in clan SC of serine proteases. It appears to have no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds 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 correlates with ADHD.¹⁵, SNP: rs272000 116372265; Within 50 kb downstream of DPP10 with p: 9.10E-06¹²⁰ One study found a correlation with ADHD for variant cg19651219 but not for variants cg22670147, cg19651219, cg24654266, cg21322022, cg00089091, or cg19211931¹¹⁷

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 protein KCNC2 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. Based on sequence similarity, this gene is similar to the Shaw subfamily of the Shaker gene family of Drosophila.
KCNC2 is associated with

• Developmental and epileptic encephalopathy 103
• extratemporal epilepsy

Related signaling pathways:

• Integration of the 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 sustained high-frequency firing in central nervous system neurons. 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 migrate in response to their electrochemical gradient. The channel alternates between open and closed conformation in response to the voltage difference across the membrane. May form functional homotetrameric and heterotetrameric channels containing variable portions of KCNC1 and possibly other family members; channel properties depend on the nature of the alpha subunits that are part of the channel. Channel properties can be modulated either by 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 channel activation and deactivation of delayed rectification potassium channels (By similarity). Contributes to the firing of sustained trains of very short action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic neurons (SCN), and hippocampal and neocortical interneurons. The frequency of the sustained maximal action potential in hippocampal inhibitory interneurons is negatively modulated by histamine H2 receptor activation in response to phosphorylation by cAMP and protein kinases (PKA). Plays a role in maintaining the reliability of synaptic transmission in neocortical GABA-ergic interneurons by producing action potential (AP) repolarization at nerve terminals, reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for synchronization of long-distance gamma oscillations 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 manner¹²¹

One study found KCNC2 (variant rs17114649) to be one of 96 ADHD candidate genes.²

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 of the S9B family in Clan SC of serine proteases. DPP6 has no detectable protease activity, most likely due to the absence of the conserved serine residue normally present in the catalytic domain of serine proteases. However, it binds specific voltage-gated potassium channels and alters their expression and biophysical properties.¹²²
DPP6

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

Diseases associated with DPP6 are:

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

One study found this gene to be one of the 51 most likely gene candidates 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 voltage-dependent permeability of potassium ions in excitable membranes. KCNC1 influences dopamine-DARPP32 feedback to the cAMP pathway.¹²³
Alternative splicing appears to result in two isoforms with different C termini.
Diseases associated with KCNC1 are epilepsy, Progressive Myoclonic 7, and Spinocerebellar Ataxia 13.

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

• SNP: rs3893215 position: 7721406; In intron of KCNC1¹²⁰
  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 protein KCNIP4 is a member of the family of voltage-dependent potassium (Kv) channel-interacting proteins (KCNIPs), which belong to the recoverin branch of the EF-hand superfamily. KCNIP family members are small calcium-binding proteins with EF-Hand-like domains that differ from each other by the N-terminus. They are integral subunit components of native Kv4 channel complexes. They may regulate A-type currents and thus neuronal excitability in response to changes in intracellular calcium. KCNIP4 also interacts with presenilin. KCNIP4 is involved in cardiac excitation conduction, regulation of nuclear beta-catenin signaling, and transcription of target genes.¹²⁴
KCNIP4 is associated with

• Synovial angioma
• congenital capillary malformations

OMIM: POTASSIUM CHANNEL-INTERACTING PROTEIN 4, KCNIP4

• SNP rs876477 position: 20766026; intron of KCNIP4¹²⁰
  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 cytosolic voltage-gated potassium (Kv) channel interaction proteins (KCNIPs) family of neuronal calcium sensor (NCS) EF hand calcium-binding proteins. They associate with Kv4 alpha subunits to form native Kv4 channel complexes. KCNIP1 can regulate fast inactivating (A-type) currents and thus 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. KCNIP1 modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents in vitro. KCNIP1 increases the presence of KCND2 at the cell surface.¹²⁵
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 position: 170075495; intron of KCNIP1 correlates with ADHD.¹²⁰¹²⁶

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 adds the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. ALG10 thereby transfers the terminal glucose from dolichylphosphate glucose (Dol-P-Glc) to the lipid-linked 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.¹²⁷
ALG10 is associated with

• Long Qt syndrome 2
• Toxic myocarditis

Related signaling pathways:

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

Paralog: ALG10B

One study found ALG10 rs1843014) as one of 96 ADHD candidate genes.²

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 in the adhesion receptor subfamily. ADGRL3 regulates synaptic function and serves to maintain it in brain regions that mediate locomotor activity, attention, and place and path 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 proteolysis site) resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with considerable similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound to the cell membrane. ADGRL3 plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3, which are expressed on the surface of adjacent cells. ADGRL3 plays a role in the development of glutamatergic synapses in the cortex. ADGRL3 is important in determining connectivity rates between principal neurons in the cortex.¹²⁸
ADGRL3 is associated with

• Sialuria
• Amed syndrome, Digenic

Related signaling pathways:

• GPCRs, class B secretin-like
• GPCRs, other
• 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 provide an animal model for ADHD.¹²⁹ ADGRL3-KO mice show:¹³⁰

• Hyperactivity in a new environment and on cocaine
  - increased dopamine and serotonin levels in the striatum
• altered dopamine and serotonin receptor expression
  - altered expression of DAT, Calcium signaling, and other cell adhesion proteins.
  ADGRL3 is involved in regulating the amount, duration, and frequency of DA release in the neostriatum (caudate-putamen).¹³⁰

ADGRL3 is a candidate gene for ADHD.^5131132133
ADGRL3 binds to Gαi1, Gαi2, Gαs, Gαq, and Gα13. In particular, gene variants that cause impaired Gα13 binding appear to be relevant in ADHD.¹³⁴ SNPs in ADGRL3 showed a correlation with ADHD symptom severity and a potential pleiotropic effect on different domains of ADHD severity.¹³⁵ ADGRL3 gene variants interact with gene variants on chromosome 11q (in a region spanning the NCAM1, TTC12, ANKK1, and DRD2 genes) and dramatically increase ADHD risk and severity in young children.^136137138131 A combination of ADGRL3 rs65511665 and a haplotype in 11q increases ADHD risk 2.5-fold.¹³⁹
ADGRL3 rs2345039 is predictor of ADHD-C with persistence of symptoms into adolescence¹³⁶
ADGRL3 rs65511665 correlates with increased ADHD prevalence and a highly comorbid subtype with disruptive behaviors.¹³⁸¹⁴⁰ ADGRL3 rs65511665 correlates with response to stinulants ¹³⁸¹⁴⁰

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 family of receptors. The proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for processing by proprotein convertase, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The Vacuolar Protein Sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is highly expressed in the brain.¹⁴¹
SorCS is expressed in a unique transient and dynamic pattern in regions where cells are proliferating and in areas where differentiated cells are already present, including the cortex, VTA, and globus pallidus. Expression of SorCS begins at the onset of differentiation of dopaminergic neurons and declines to low levels in adulthood. The VTA projects dopaminergically to the basal ganglia, amygdala, and cerebral and piriform cortex. These areas are also characterized by the presence of dopaminergic neurons and express SorCS. This suggests a possible function of SorCS in the development of dopaminergic pathways.¹⁴²
SORCS3 is associated with

• ADHD
• Alzheimer
  • silencing of the SORCS3 gene in cell cultures resulted in increased processing of the amyloid precursor protein

Related Signal Paths:

• Neuropeptide receptor activity

Paralog: SORCS1

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁴³¹⁴⁴

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

The protein DIRAS2 (Di-Ras2) belongs to a branch of the functionally diverse Ras superfamily of monomeric GTPases. Ras 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 shows low GTPase activity and is predominantly present in the GTP-bound form. In fact, it is an open question whether DIRAS2 is regulated by GTP binding at all.¹⁴⁵ DIRAS2 is particularly highly expressed in inferior raphe serotonin neurons¹⁴⁶, which may indicate a contribution to regulation of the caudal serotonergic system.
DIRAS2 inhibited colorectal cancer cell proliferation and affected cell cycle protein expression. DIRAS2 blocked the signaling pathways of NF-kB, resulting in G0/G1 arrest. DIRAS2 interacted with regulatory subunit 2 of the 26S proteasome (PSMD2), which is not an ATPase, facilitating proteasome-mediated degradation of DIRAS2. DIRAS2 is degraded by PSMD2 in a proteasome-mediated manner. DIRAS2 inhibited nuclear expression of P65 in both RKO and HT29 cells.¹⁴⁷ DIRAS2 decreased 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) and localize to the nucleolus and act as a tumor suppressor.¹⁴⁸

DIRAS2 is expressed in the human brain mainly in the hippocampus, PFC, ACC and amygdala.¹⁴⁵¹⁴⁹ During brain development, Diras2 increases sharply in mice from prenatal to late postnatal stages. Diras2 is expressed in glutamatergic and catecholaminergic neurons.¹⁴⁹

DIRAS2 functions as a tumor suppressor gene in cutaneous skin melanoma by inhibiting Wnt/β-catenin signaling. It is also associated with immune infiltration in cutaneous skin melanoma,¹⁵⁰ with papillary thyroid microcarcinoma¹⁵¹ and colorectal carcinoma (the most common gastrointestinal cancer) .¹⁴⁷

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

DIRAS2 blocks the action of Nf-kB.¹⁴⁷
This may represent a pathway to dopamine, as Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁵²

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone binding
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity on caffeine.

DIRAS2 is a candidate gene for ADHD.¹⁴⁹ Indications for a correlation with ADHD were found in:¹⁴⁵

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

DIRAS2 is not only associated with ADHD, but also with bipolar disorder and Parkinson’s disease. A cross-disorder analysis for all disorders together (ADHD, bipolar and Parkinson’s disease) showed a 13% risk increase for the rs1412005 T allele.¹⁴⁵
The association with ADHD and Parkinson’s disease may suggest that DIRAS2 affects the dopaminergic system.

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

The protein TLE1 is part of the beta-catenin-TCF complex. It is found in the cytosol and nucleoplasm.
TLE1:¹⁵³

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

TLE1 is associated with the diseases

• Nuclear binding factor Acute myeloid leukemia
• Glomerular tumor

TLE1 impaired NOD2 and thereby Nf-kB signaling in the liver.¹⁵⁴
This may represent a pathway to dopamine, as Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁵²

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone binding
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity on caffeine.

OMIM: TLE1, TRANSDUCIN-LIKE ENHANCER OF SPLIT 1

For TLE1, one study found a change in expression in ADHD.¹ TLE1 had already attracted attention as a candidate gene for ADHD in another study.¹⁵⁵

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 protein FERMT3 is a member of the Kindlin family of proteins that mediate protein-protein interactions in integrin activation, thereby playing 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 and 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.¹⁵⁶ 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.¹⁵⁷
FERMT3 is associated with

• Leukocyte adhesion deficiency, type Iii
• Kindler syndrome

Inhibition of NF-kappa-B may provide a pathway to dopamine because Nf-kB regulates striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) expression in the striatum. NF-kappaB p50 subunit KO mice (Nf-kB-p50 KO mice) showed in the striatum:¹⁵²

• more A2AAR
• less A1AR
• less D2R mRNA
• reduced [(3)H]-methylspiperone binding
• increased G(alphaolf) and G(alphas) proteins
  • these transmit A2AAR signals
    -reduced G(alphai1) protein
    this forwards signals from A1AR and D2R

Nf-kB p50-KO mice showed increased locomotor activity on caffeine.

One study found this gene to be one of the 51 most likely gene candidates 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; p53-induced death domain protein, LRDD, LEUCINE-RICH REPEATS- AND DEATH DOMAIN-CONTAINING PROTEIN; 11p15.5

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

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

Related Signal Paths:

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

The timing of Gli1 and Sonic Hedgehog expression segregates midbrain dopamine neurons.¹⁵⁸ Gli1 protects nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration in Parkinson’s disease models.¹⁵⁹

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 development and digital development, as well as in central nervous system and gastrointestinal development. GLI1 mediates SHH signaling. GLI1 plays a role in cell proliferation and differentiation via its role in SHH signaling.
[Isoform 2]: Acts as a transcriptional activator but activates a different group of genes than isoform 1. Isoform 2 activates the expression of CD24, in contrast to isoform 1. Isoform 2 mediates SHH signaling and promotes cancer cell migration.

OMIM: LRDD / PIDD1, LEUCINE-RICH REPEATS- AND DEATH DOMAIN-CONTAINING PROTEIN; 11p15.5

One study found increased expression and decreased methylation of GLI2 in ADHD.¹⁰³

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 protein DGKH 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 distinct regulatory domains. Diacylglycerol kinases (DGKs) are involved in the regulation of intracellular concentrations of diacylglycerol and phosphatidic acid. DGKH likely acts as a central switch between signaling pathways activated by diacylglycerol and phosphatidic acid with distinct 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 induced by EGF. DGKH regulates the recruitment of RAF1 and BRAF from the cytoplasm to membranes and their heterodimerization.¹⁶⁰
DGKH is associated with

• Bipolar disorder
• Nephrolithiasis

Related Signal Paths:

• downstream GPCR signaling
• Response to increased platelet cytosolic Ca2+
• 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 in mice and in the striatum in humans .

In DGKH-KO mice, dopamine and the phosphorylated dopamine transporter are increased.¹⁶¹

Hains and Arnsten describe an impact of DGKH on stress regulation. Excessive dopaminergic D1 receptor stimulationimpaired prefrontal function via intracellular cAMP signaling, resulting in disruption of prefrontal networks, whereas excessive noradrenergic stimulation of alpha1 receptors impaired prefrontal function via intracellular phosphatidylinositol-protein kinase C signaling. DISC1, RGS4, and DGKH normally serve to inhibit intracellular phosphatidylinositol-protein kinase C signaling and thus serve as brakes on intracellular signaling pathways. Mutations leading to loss of adequate function of these genes are likely to weaken endogenous regulation of these signaling pathways, explaining the susceptibility to stress and severe loss of PFC regulation of behavior, thought, and affect (together with thought disorder, disinhibition, and impaired working memory) in the diseases associated with these gene mutations.¹⁶²

Paralog: DGKD

A DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with adult ADHD, bipolar disorder (rs1170169 and rs9525580), and depression, whereas the complementary AGC haplotype was protective.¹⁶³ One study found no evidence of environmental gene interactions in relation to rs994856/rs9525580/rs9525584 GAT in ADHD.¹⁶⁴

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 influences¹⁶⁵

• Endocytosis
• Cell signaling
• Cell proliferation
• Cell migration
• Cell adhesion
• Cell death
• Cholesterol homeostasis
• Albumin excretion in urine
• Embryo implantation
• promotes angiogenesis and vasculogenesis by inducing VEGFA through a HIF1A-dependent pathway
• inhibits caveolin-1 by increasing lysosomal degradation
• activates PTK2, thereby regulating focal adhesion density, F-actin conformation, and cell adhesiveness
• 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.¹⁶⁶ This can trigger oxygen deprivation. Hypoxia, in turn, is known to cause alteration of the dopamine system. For example, oxygen deficiency during birth is a possible cause of ADHD.

EMP2 is associated with the diseases

• nephrotic syndrome
• genetic steroid-resistant nephrotic syndrome

Related Paths:

• Protein kinase binding
• Kinase binding

Paralog: PMP22

One study found this gene to be one of the 51 most likely gene candidates 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 to 22q12.3, a possible schizophrenia susceptibility locus, and the established neurobiological role of synapsins, this family member may represent a candidate gene for schizophrenia. The TIMP3 gene is located in an intron of this gene and is transcribed in the reverse direction.¹⁶⁷

SYN3 is associated with

• Sorsby fundus dystrophy
• Fundus Dystrophy

Related Signal Paths:

• Neurotransmitter release cycle
• Transmission via chemical synapses
• Synaptogenesis

Paralog: SYN2

Syn III controls the earliest stages of dopaminergic neuron development in vertebrates and mammals.Polymorphisms in the synapsin III (Syn III) gene are associated with ADHD and affect MPH responding. MPH can bind SYN3. The observed SYN3 polymorphism appears to influence ADHD onset and MPH response by affecting BDNF-dependent development of dopaminergic neurons.¹⁶⁸

1.318. SYN1, Synapsin 1¶

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

Synapsins encode neuronal phosphoproteins that associate with the cytoplasmic surface of synaptic vesicles. Synapsins are characterized by common protein domains and are involved in synaptogenesis and modulation of neurotransmitter release.
Synapsin-I (SYN1) is a presynaptic phosphoprotein critical for synaptogenesis and synaptic plasticity. SYN1 plays a role in regulating 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 in the nerve terminal¹⁶⁹

SYN1 is associated with:

• X-linked disorders with primary neuronal degeneration, mainly affecting males.
  • Rett syndrome

A study of 31 individuals found 22 different SYN1 variants¹⁷⁰

Syn1 abnormalities correlate with:¹⁷⁰

• ASD or ADHD in 91% of those affected
• Epilepsy in 82
  • mainly tonic-clonic or focal seizures with disturbances of consciousness
  • Reflex seizures are one of the most representative clinical manifestations associated with SYN1
  • Trigger:
    • Contact with water (> 50 %)
    • Rubbing with a towel
    • Fever
    • Brushing teeth
    • Fingernail cutting
    • Fall asleep
    • Watching other people shower or bathe
    • Hyperpnea
    • Emotions
    • Light
    • Stroboscope
    • Digestive problems
    • Bowel movement
• mental disability at 77
  • correlates with early age of seizure onset
• Developmental delay at 70

The molecular spectrum of SYN1 variants is broad

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

Norepinephrine¶

Noradrenaline 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 gene for ADHD.¹²¹²⁰⁵

Norepinephrine action¶

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

OMIM: ALPHA-1A-ADRENERGIC RECEPTOR; ADRA1A

The HES1 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.017.⁶

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

OMIM: ALPHA-2A-ADRENERGIC RECEPTOR; ADRA2A

ADRA2A is a candidate gene for ADHD.⁵¹²⁰⁶⁴

None of the ADRA2A polymorphisms MspI and DraI correlated significantly with response to MPH as a whole. However, carriers of the G allele of the MspI polymorphism showed a correlation with significant improvement in inattention symptoms.¹⁷¹

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

OMIM: ALPHA-2C-ADRENERGIC RECEPTOR

Source¹²⁰

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

OMIM: BETA-2-ADRENERGIC RECEPTOR; ADRB2

The ADRB2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.013.⁶

Norepinephrine degradation¶

Norepinephrine reuptake¶

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

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

The noradenaline transporter reuptakes more dopamine than noradrenaline in the PFC. See therefore above under dopamine reuptake.

Of the four polymorphisms of the NET gene

• rs5569
• rs28386840
• rs2242446
• rs3785143
  showed carriers of the T-allele of the polymorphism rs28386840
• significantly more frequent responding to MPH
• significantly greater improvement in hyperactive-impulsive symptoms
  than the carriers of the other polymorphisms.
  ¹⁷¹

Serotonin¶

Serotonin synthesis¶

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

Tryptophan hydroxylase is a candidate gene for ADHD.⁵

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

OMIM: Tryptophan hydroxylase-1 gene; TPH1

One study found that the rare 218A-6526G haplotype of TPH1 was significantly more likely not to be transmitted in subjects with ADHD.¹⁷²

Another study failed to find involvement of the more common haplotypes of TPH1 or TPH2 in ADHD-C.¹⁷³

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

OMIM: Tryptophan hydroxylase-2 gene, TPH2

TPH2 is a candidate gene for ADHD.¹²⁰

The TPH2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.003.⁶ Another study could not confirm this for either TPH1 or TPH2.¹⁷³

Stress naive TPH2-/- mice (TPH2-KO mice) showed decreased dopamine levels in hippocampus and PFC.¹⁷⁴
In TPH2+/- mice, stress resulted in decreased dopamine levels:¹⁷⁵

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

The changes in the dopaminergic system of stressed TPH2+/- mice were markedly different from those in TPH2+/+ animals and strongly resembled those in TPH2-/- mice.

Stressed TPH2-/- mice showed no particular changes in norepinephrine levels in amygdala, PFC, hippocampus, dorsal raphe nuclei, or striatum. They merely showed (as did TPH2+/+ mice) the usual increased norepinephrine levels in the PFC, hippocampus, and striatum compared with nonstressed mice of the respective genotype.¹⁷⁵

The TPH2 variant rs17110747 showed behavioral and cognitive symptoms of ADHD only in females. There was a highly significant transmission of the G allele from parents to affected girls. In addition, girls with the G/G genotype (rs17110747) responded better to placebo when assessed by parents.¹⁷⁶

Serotonin effect¶

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.¹²⁰⁵

1.51. HTR1E, serotonin receptor 1E (chromosome 6q14.3)¶

Another name: 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 = 0.051.⁶

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 gene for ADHD.¹²⁰⁵

Serotonin degradation¶

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.¹²⁰⁵¹²

Serotonin Metablization¶

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 at the same time rate-determining reaction step in the degradation of tryptophan.

The tryptophan 2,3-dioxynase gene is a candidate gene for ADHD.¹⁷⁷

Steroids¶

1.19. Androgen receptor (chromosome Xq11-q12)¶

The androgen receptor gene is a candidate gene for ADHD.¹⁷⁷

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 protein SLC6A12 is involved in monocarboxylic acid transport. SLC6A12 is thought to be localized in the plasma membrane and is likely to be an integral component of the plasma membrane. SLC6A12 is thought to be active in neuron projection. SLC6A12 transports betaine and GABA. It is likely to be relevant in the regulation of GABA-ergic transmission in the brain through the reuptake of GABA into presynaptic terminals and in osmotic regulation. Four 12-TM domain transporters have been identified that are localized in neurons and glia.¹⁷⁸
SLC6A12 is associated with

• Spinocerebellar ataxia 11
• Reflex epilepsy

SLC6A12 is a candidate gene for ADHD.¹⁷⁹

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.¹⁸⁰

1.22. GABA receptor-alpha3 (chromosome Xq28)¶

OMIM: GABA receptor alpha3 gene

GABA receptor-A3 is a candidate gene for ADHD.⁵

OMIM indicates function in relation to physical and psychological pain sensing as well as motor impairment and tolerence.

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

OMIM: GABA receptor beta 3 gene

GABA receptor-B3 is a candidate gene for ADHD.⁵

OMIM points out that GABA receptors are zinc-controlled and a particularly zinc-insensitive polymorphism is known. OMIM does not mention ADHD, but autism, to which ADHD has a high comorbidity.
There are thoughts that ADHD and autism may share common neurological roots.¹⁸¹
Zinc deficiency can cause ADHD (similar) symptoms.

1.35. CDH13, Cadherin13 (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 affects GABAergic function in the hippocampus and cognition.¹⁸²
The prote9in CDH13 is a member of the cadherin superfamily. CDH13 is localized to the surface of the cell membrane and is anchored by a GPI unit rather than a transmembrane domain. CDH13 lacks the cytoplasmic domain characteristic of other cadherins, so it is not thought 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 due to oxidative stress. Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner when cells are joined; cadherins may therefore contribute to the sorting of heterogeneous cell types. They may act as a negative regulator of neuronal cell growth.¹⁸³
CDH13 is associated with

• Resistance to atherosclerosis
• many cancers (CDH13 is hypermethylated there)
• Vacterl Association
• Seminoma

Paralog: CDH2

OMIM: Cadherin13 (CDH13) gene

CDH 13 is a candidate gene for ADHD.¹⁸⁴

• SNP rs7187223, position 81015234; Intergenic, within 203 kb upstream from CDH13¹²⁰
  P: 5.21E-05.
• SNP s116411, position 81304438; In Intron of CDH13¹²⁰
  P: 7.40E-06
• SNP rs6565113, position 81665146; intron of CDH13¹²⁰
• One study found CDH13 (variant rs8055161) to be one of the 20 most likely among 96 candidate genes²

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 membranous 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, synapse function, and neuronal morphology, including dendritic tree branching and spine formation. KIF21B plays a role in learning and memory. KIF21B is involved in the transmission of the gamma-aminobutyric acid (GABA(A)) receptor to the cell surface.

One study found this gene to be one of the 51 most likely gene candidates 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.¹⁸⁵

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 SHRNA4 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.05.⁶¹²⁰

1.212. LYPD1, LY6/PLAUR Domain Containing 1¶

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

The protein LYPD1 is thought to act as a modulator of nicotinic acetylcholine receptor (nAChRs) activity, having acetylcholine receptor binding activity and acetylcholine receptor inhibitory activity.LYPD1 increases receptor desensitization and decreases affinity for ACh of alpha-4:beta-2-containing nAChRs in vitro. LYPD1 may play a role in the intracellular transport of alpha-4:beta-2- and alpha-7-containing nAChRs and inhibits their expression at the cell surface. LYPD1 is involved in posttranslational modification: synthesis of GPI-anchored proteins and metabolism of proteins. LYPD1 may be involved in the control of anxiety¹⁸⁶
LYPD1 is associated with

• Arthrogryposis, distal, type 2A
• melanotic medulloblastoma

Paralog: LYPD2

One study found LYPD1 (variant rs7561232) to be one of 96 ADHD candidate genes.²

Choline degradation¶

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 protein SLC5A7 is a sodium and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. SLC5A7 transports choline from the extracellular space to presynaptic terminals for acetylcholine synthesis. Increased choline uptake results from increased density of this protein in synaptosomal plasma membranes in response to 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 ion- and chloride ion-dependent.¹⁸⁷
SLC5A7 associated with

• Myasthenic syndrome, congenital, 20, presynaptic
• Neuronopathy, distal hereditary motor, type Viia (autosomal dominant distal hereditary motor neuronopathy type VIIA)
• Depression
• ADHD
• Schizophrenia

Paralog: SLC5A2

SLC5A7 - coding variant Ile89Val (rs1013940) has a two- to threefold frequency in ADHD sufferers (n = 100; P = 0.02) and is supposed to correlate with ADHD-C (OR = 3.16; P = 0.01), whereas coding variant SNP 3’ (rs333229) was significantly less frequent in ADHD sufferers than in nonaffected individuals (n = 60; P = 0.004).¹⁸⁸

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 protein SLC44A1 is a choline transmembrane transporter. SLC44A1 is involved in choline transport and transmembrane transport. SLC44A1 is found in several cellular components, including the cytosol, mitochondrion, and nucleoplasm. SLC44A1 is involved in high-grade gliomas. SLC44A1 is involved in membrane synthesis and myelin production.¹⁸⁹
SLC44A1 is associated with

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

Paralog: SLC44A3

One study found SLC44A1 (variant rs10991581) to be one of 96 ADHD candidate genes.²

Glutamate¶

1.39. GRM1, glutamate receptor metabotropic 1 (chromosome 6p24-3)¶

OMIM:Glutamate receptor metabotropic 1 (GRM1) gene

GRM1 is a candidate gene for ADHD.¹⁹⁰

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

Other names: GluK3; GLUR7; Glutamate Receptor Ionotropic, 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 variety 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 not certain whether the subunit encoded by this gene is subject to RNA editing like the other two family members (GRIK1 and GRIK2). Kainate receptors have been identified both pre- and postsynaptically. The glutamate receptor GRIK2 binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.¹⁹¹
GRIK3 is associated with:

• Schizophrenia (A Ser310Ala polymorphism)
• there are conflicting reports about its association with the pathogenesis of delirium tremens in alcoholics
• Depersonalization disorder

Paralog: GRIK2

One study found GRIK3 (variant rs1032722) to be one of 96 ADHD candidate genes.²

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

One study investigated the GRIK1 variants rs363504 and rs363538 by measuring GRIK1 expression in peripheral blood.¹⁹²

• The subjects and their fathers had a higher frequency of the rs363504 ‘CC’ and rs363538 ‘CA’ genotypes.
• Rs363504 ‘C’ and rs363538 ‘A’ were passed from mother to subjects.
• Rs363504 ‘TT’ and rs363538 ‘AA’ correlated with higher hyperactivity scores.
• Rs363504 ‘TT’ and rs363538 ‘CC’ correlated with improvement in hyperactivity and inattention, respectively, by MPH.
• GRIK1 expression was significantly downregulated in the subjects.

1.34. GRM5, glutamate receptor metabotropic 5 (chromosome 11q14..2 - 14.3) (33, p. 55)¶

OMIM: Glutamate receptor metabotropic 5 (GRM5) gene

GRM5 is a candidate gene for ADHD.¹⁹⁰⁵ One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

1.38. GRM7, glutamate receptor metabotropic 7 (chromosome 3p26.1)¶

OMIM: Glutamate receptor metabotropic 7 (GRM7) gene

GRM7 is a candidate gene for ADHD.¹⁹⁰

The GMR7 rs3792452 polymorphism affects methylphenidate response in children with ADHD.¹⁹³

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 of the solute carrier 9 family of proteins. SLC9A9 is localized in the late recycling endosomes and appears to be relevant for the maintenance of cation homeostasis. SLC9A9 is involved in

• electroneutral exchange of protons against Na(+) through membranes
• Excretion of luminal H(+) from the Golgi 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 in the cell¹⁹⁴
  SLC9A9 protein counteracts endosomal acidification by alkalizing the system. SLC9A9 controls the tight pH regulation of the endosomal system and clathrin-mediated endocytosis.¹⁹⁵ SLC9A9 subsequently regulates panreceptor recycling.
  Increased SLC9A9 expression in mouse astrocytes¹⁹⁵
• increased surface localization and recycling of the **glutamate transporter **(GLAST)
• increased the uptake of glutamate
  Increased SLC9A9 expression in glioblastoma multiforme (GBM) cell lines¹⁹⁵
• increased the surface localization of the endothelial growth factor receptor (EGFR)
• increased the tumor invasiveness
  Increased SLC9A9 expression¹⁹⁵
• increased internalization and recycling of transferrin receptors in HEK293, brain microvascular endothelial cells, and glioma cells
  By regulating transferrin receptor recycling, SLC9A9 plays an important role in iron metabolism.
  **Iron deficiency **causes¹⁹⁵
• increased SLC9A9 expression in human brain microvascular endothelial cells (hBMVECs) that form the blood-brain barrier (BBB)
• increased the **iron uptake **across the blood-brain barrier through
  • Up-regulation of transferrin receptor expression
  • Increase of the endosomal pH value
  • enhanced translocation of TfRs to the hBMVEC membrane
    Amino acid deficiency causes¹⁹⁵
• increased SLC9A9 expression in immortalized hypothalamic neurons and primary cortex cells
  SLC9A9 regulates cellular nutrients and cellular metabolism.¹⁹⁵.
  SLC9A9 is associated with:
• ADHD¹⁹⁶¹⁹⁷
• Autism 16¹⁹⁶
  • An ASD nonsense mutation in SLC9A9, R423X, did not generate detectable levels of SLC9A9, suggesting an overall loss of SLC9A9 functional networks in ASD. Moreover, 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), supporting a role for 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

One study identified 100 proteins that interact with SLC9A9. These proteins were enriched in known functional pathways for SLC9A9:¹⁹⁷

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

The ADHD-associated mutation A409P significantly altered the interactions of SLC9A9 with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling.¹⁹⁷
The SLC9A9 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.01.⁶ Another study found SLC9A9 (variant rs7621206) to be one of the 20 most likely among 96 candidate genes.² Another study also found SLC9A9 to be the most highly correlated of the genes studied.¹⁵,

Cannabinoids¶

1.37. CNR1, cannaboid receptor 1 (chromosome 6q14-q15)¶

OMIM: Cannaboid receptor 1 (CNR1) gene

CNR1 is a candidate gene for ADHD.¹⁸⁴

Traceamine¶

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 = 0.008.⁶

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

For SLC6A9, several studies found an alteration in expression in ADHD.¹¹⁰⁴

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 neurotransmission, antimicrobial and antitumor activities, among others. Nitric oxide exhibits many neurotransmitter properties in the brain and peripheral nervous system. It is involved in

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

OMIM: Nitric Oxide synthase 1 (NOS1) gene

Nitric oxide (NO) has been implicated in schizophrenia, ADHD, and possibly mood disorders:¹⁹⁸

Genetically determined decreased NO signaling in the PFC is associated with schizophrenia and cognition problems. Here, NOS1 as well as its interaction partner NOS1AP play a role.
Reduced NOS1 expression in the striatum due to a length polymorphism in the NOS1 promoter (NOS1 ex1f-VNTR) correlates with impulsivity.
Associations of NOS1 with mood disorders is possible. NO metabolites in blood may serve as biomarkers for major depression and bipolar disorder. .

NOS 1 (short allele) is a candidate gene for increased impulsivity and thus ADHD.¹⁸⁴¹⁹⁹

Neurotransmitter storage and release¶

1.114. CPLX2, Complexin 2¶

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

CPLX2 is a cytosolic protein and plays a role in the exocytosis of synaptic vesicles. It binds to and disrupts syntaxin, a part of the SNAP receptor, allowing the release of transmitters. CPLX2 inhibits the formation of synaptic vesicle clusters at the active zone to 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.²⁰⁰

CPLX2 is associated with

• Schizophrenia
• Epilepsy, familial temporal lobe, 7.

One study found this gene to be one of the 51 most likely gene candidates 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 thus may modulate the formation of functional SNARE complexes and exocytosis.²⁰¹
STXBP6 is associated with:

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

Paralog: EXOC1

One study found STXBP6 (variant rs17200947)as one of 96 ADHD candidate genes.²

1.242. MYO5B, Myosin VB¶

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

The protein MYO5B may be involved in plasma membrane recycling along 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 complex with RAB11A and RAB11FIP2 for transport of NPC1L1 to the plasma membrane. MYO5B, together with RAB11A, is involved in CFTR transport to the plasma membrane and TF (transferrin) recycling in non-polarized cells. MYO5B, together with RAB11A and RAB8A, is involved in epithelial cell polarization. MYO5B, together with RAB25, regulates transcytosis.²⁰²
MYO5B is associated with

• Diarrhea 2
• Microvillus atrophy, with or without cholestasis
• Microvillus inclusion disease

Paralog: MYO5A

One study found MYO5B (variant rs1787319) to be one of 96 ADHD candidate genes.²

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 protein TRAPPC11 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 Golgi²⁰³
TRAPPC11 is associated with

• Muscular dystrophy
• Limb girdle, autosomal recessive 18
• Intellectual disability-hyperkinetic movement-truncal ataxia syndrome

Related metabolic pathways:

• Vesicle-mediated transport
• Rab regulation of trafficking.

UniProtKB/Swiss-Prot summary for TRAPPC11 gene
Involved at a very early stage in transport from the endoplasmic reticulum to the Golgi apparatus. ( TPC11_HUMAN,Q7Z392 )

One study found TRAPPC11 (variant rs10018951) to be one of 96 ADHD candidate genes.²

Brain development¶

1.33. NDE1, Nuclear distribution gene E homologue 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; Epididymis 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) family of proteins, localized to the centrosome and required for:²⁰⁴

• Cortex development
• Centrosome duplication
• Formation and function of the mitotic spindle
• Microtubule organization
• Mitosis
• neuronal migration
• Regulation of dynein function

NDE1 is associated with

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

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.¹⁸⁵

1.106. MAP1B, Microtubule Associated Protein 1B¶

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

The protein MAP1B belongs to the family of microtubule-associated proteins that are thought to be involved in microtubule assembly, which is an essential step in neurogenesis. MAP1B is a precursor polypeptide that presumably forms the final heavy chain of MAP1B and the light chain of LC1 after proteolytic processing. MAP1B knockout mouse studies suggest an important role in nervous system development and function. MAP1B facilitates tyrosination of alpha-tubulin in neuronal microtubules. Phosphorylated MAP1B appears to play a role in the cytoskeletal changes associated with neurite outgrowth. MMAP1B acts as a positive cofactor in DAPK1-mediated autophagic vesicle formation and membrane blebbing.²⁰⁵
MAP1B is associated with

• Periventricular nodular heterotopia 9
• Deafness, Autosomal Dominant 83

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

1.107. MOBP, Myelin-Associated Oligodendrocyte Basic Protein¶

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

MOBP is associated with frontotemporal dementia and cocaine abuse

One study found this gene to be one of the 51 most likely gene candidates for ADHD.²⁰⁶

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

The proteins astrotactin-1 and 2 (ASTN-1 and ASTN-2) are integral membrane perforin-like proteins. They play a critical role in neurodevelopment. Genetic variations in these proteins are associated with a number of neurodevelopmental disorders and other neurological pathologies, including advanced onset of Alzheimer’s disease. ASTN-2 (unlike ASTN-1) binds inositol triphosphates , suggesting a mechanism for membrane recognition or regulation of its activity by secondary messengers.

OMIM: ASTROTACTIN 2; ASTN2

• SMP: rs10983238 position: 118373504; In intron of ASTN2¹²⁰
  p: 1.37E-07
  One study found this gene to be one of the 51 most likely gene candidates 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 protein TCF4 is a basic helix-loop-helix transcription factor. It recognizes an ephrussi box (“E-box”) binding site (“CANNTG”). TCFG4 is widely expressed and may play an important role in nervous system development. 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
• endothelial corneal dystrophy of Fuchs

One study found this gene to be one of the 51 most likely gene candidates 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 protein TLL2 is astacin-like zinc-dependent metalloprotease and member of the metzincin family subfamily. TLL2 is a predominant protease and specifically processes pro-lysyl oxidase. TLL2 is required for embryonic development and affects the development of dorsal-ventral patterning and dre skeleton formation.

TLL2 is associated with

• Powassan encephalitis
• Louping Ill.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

1.117. TENM4, Teneurin Transmembrane Protein 4¶

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

The protein TENM4 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 oligodendrocyte differentiation and cellular process formation and myelination of small diameter axons in the central nervous system (CNS). TENM4 promotes activation of focal adhesion kinase. TENM4 may function as a cellular signal transducer.

TENM4 is associated with tremor.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

1.91. ANK3, ANKYRIN 3¶

Other names: Ankyrin 3; Ankyrin 3, Node Of Ranvier (Ankyrin G); Ankyrin-G; Ankyrin-3; Ankyrin-3, Node Of Ranvier; ANKYRIN-G; MRT37; ANK-3

The scaffold protein ankyrin-3 is immunologically distinct from the ankyrins ANK1 and ANK2. It is found at the axonal initial segment and at the nodes of Ranvier of neurons in the central and peripheral nervous system. Within the nodes of Ranvier, where action potentials are actively transmitted, ANK3 is an intermediate binding partner for neurofascin and voltage-gated sodium channels. ANK3 is required for the normal accumulation of voltage-gated sodium channels at the axon hillock and for the initiation of action potentials.²⁰⁷
ANK3 is found in the human brain primarily in the cerebellum and, less densely, in the PFC, hippocampus, corpus callosum, and hypothalamus. ANK3 plays a central role in regulating the localization of ion channels, membrane transporters, cell adhesion molecules, and cytoskeletal proteins. ²⁰⁸
Associations are found between ANK3 and dopamine.²⁰⁹²¹⁰ ANK3 is an essential component of AMPAR-mediated synaptic transmission and maintenance of spine morphology. ANK3 promotes the stability of somatodendritic GABA-ergic synapses in vitro and in vivo by counteracting endocytosis of GABAA receptors.²¹¹
ANK3 is expressed by oligodendrocytes and is found on the glial rather than axonal side of nodes.²¹² ANK3 regulates the β-catenin/Wnt signaling pathway involved in bipolar disorder.²¹³ A short ANK3 isoform is localized in dendritic spines and regulates NMDA receptor-dependent plasticity.²¹⁴ ANK3 accumulates in dendritic spines after chronic lithium treatment.²¹⁵ In bipolar disorder, ANK3 mRNA is increased in blood, although no increased expression was found in brain.²¹⁶

ANK3 and stress
Prenatal stress affects the interaction of ANK3 protein with PSD95. ANK3 appears to influence the effects of early childhood stress on the development of psychiatric disorders.²¹⁷
Heterozygous ANK3+/- mice as well as mice in which ANK3 was deactivated in the dentate gyrus showed²¹⁸

• reduced anxiety
  • reversible by chronic lithium administration
• increased reward motivation
  • reversible by chronic lithium administration
    Ank3+/- mice showed increased susceptibility to chronic stress:
• increased susceptibility to depression-like behaviors
• elevated corticosterone levels.

ANK3 is associated with

• PTSD²¹⁹
• Autism²²⁰²²¹
• Brugada syndrome, a form of cardiac arrhythmia.
• bipolar disorder
  • a.o. rs10994336, rs1938526 and rs9804190²⁰⁸
• intellectual disability.

OMIM: ANK3, ANKYRIN 3

ANK3 is associated with ADHD.¹ One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

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 testis. ANKS1B interacts with the amyloid beta protein precursor (AbetaPP) and may play a role in normal brain development and in the development of Alzheimer’s disease. Isoform 2 may be involved in the regulation of 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.²²²

ANKS1B is associated with

• Alzheimer
• pre-B-cell acute lymphoblastic leukemia

One study found this gene to be one of the 51 most likely gene candidates 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 protein EPHA7 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. The EPH subfamily receptors typically have a single kinase domain and an extracellular region containing a Cys-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 ephrin-A family ligands located on adjacent cells, resulting in contact-dependent bidirectional signal transduction into neighboring cells.
The signaling pathway downstream of the receptor is referred to as forward signaling, whereas the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Among GPI-anchored ephrin A ligands, EFNA5 is a cognitive/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 may also regulate brain development through caspase (CASP3)-dependent proapoptotic activity. Forward signaling may lead to activation of components of the ERK pathway, including MAP2K1, MAP2K2, MAPK1, and MAPK3, which are phosphorylated upon activation of EPHA7.²²³
EPHA7 is associated with

• Brachydactyly Syndactyly Syndrome
• Brachydactyly, type A4
• various carcinomas at elevated gene expressionin

Paralog: EPHA5

One study found EPHA7 (variant rs16870710) to be one of 96 ADHD candidate genes.²

1.299. SEMA6D, Semaphorin 6D¶

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

SEMA6D is a vertebrate class 6 transmembrane semaphorin. Semaphorins are a large family that includes both secreted and membrane-associated proteins, many of which are involved as inhibitors or chemorepellents in axon wayfinding, fasciculation and branching, and target selection. All semaphorins have a semaphorin domain (sema) and a PSI domain (found in plexins, semaphorins, and integrins) in the N-terminal extracellular portion. Additional sequence motifs at the C-terminus of the semaphorin domain allow classification into different subfamilies. Transmembrane semaphorins, like secreted semaphorins, can function as repulsive axon guidance markers. SEMA6D acted on dorsal root ganglion (DRG) neurons in vitro. SEMA6D may be a stop signal for DRG neurons in their target areas and possibly for other neurons as well. SEMA6D may also be involved in the maintenance and remodeling of neuronal connections.²²⁴
SEMA6D is associated with

• Cone-Rod dystrophy 10
• Kallmann syndrome

Related signal paths:

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

Paralog: SEMA6A

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁴³

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 protein Neuron Navigator 2 (NAV2) is a member of the Neuron Navigator protein family. NAV2 is widely expressed in the central nervous system (CNS), particularly in the developing cerebellum. NAV2 is critical for cytoskeletal dynamics and neurite growth²²⁵
Nav2 is associated with

• Cerebellar hypoplasia with abnormal folding due to impaired axonal outgrowth
• Corpus callosum hypo-dysgenesis
• Agenesis of the olfactory bulbs
• cellular migration deficits
• NAV2 abnormalities are usually lethal²²⁵

OMIM: NEURON NAVIGATOR 2

The SNP rs874426 position: 19526139; In intron of NAV2 was identified as an ADHD gene candidate with p: 3.75E-06.¹²⁰

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

CNNM2 is associated with

• Hypomagnesemia
• Renal and hypomagnesemia
• Seizures
• mental retardation
• Schizophrenia²²⁶
• Depression²²⁶

CNNM2 is one of the three major genes interacting with AS3MT. AS3MT rs7085104 is associated with an alteration in striatal dopamine synthesis capacity.⁹

One study found CNNM2 to be one of the 51 most likely gene candidates for ADHD.¹⁰

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 protein NTF3 belongs to the family of neurotrophins that control 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 affect the development of neurons in the embryo when expressed in the human placenta. NTF3-KO mice exhibit severe limb movement disorders. The mature peptide of this protein is identical in all mammals studied, including human, pig, rat, and mouse.UniProtKB/Swiss-Prot abstract for NTF3 appears to promote survival of visceral and proprioceptive sensory neurons.²²⁷
NTF3 is associated with

• Hypochondriasis
• diabetic polyneuropathy

Related signaling pathways:

• Apoptotic Pathways in Synovial Fibroblasts
• GPCR Pathway
• Signal receptor binding
• chemoattractive activity

Paralog: NGF

OMIM: Neurotrophin-3 (NTF3) gene

NTF3 is a candidate gene for ADHD.⁵¹²⁰

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

Other names: NT-4/5; GLC1O; 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 protein NTF4 is a member of a family of neurotrophic factors, neurotrophins, that control survival and differentiation of mammalian neurons. Expression of this gene is ubiquitous and less affected by environmental signals. While knock-outs of other neurotrophins, including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3, are lethal during early postnatal development, NTF5-KO mice show only minor cellular deficits and develop normally to adulthood. NTF4 is a target-derived survival factor for peripheral sensory sympathetic neurons.²²⁸
NTF4 is associated with

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

Related signaling pathways:

• Differentiation pathway of pluripotent stem cells
• apoptotic signaling pathway in synovial fibroblasts
• Signal receptor binding
• Neurotrophin p75 receptor binding

Paralog: BDNF

OMIM: NEUROTROPHIN 4; NTF4

NTF4 is a candidate gene in ADHD.¹²⁰

1.26. BDNF, Brain-derived-neurothropic-factor (chromosome11p14.1) (X)¶

OMIM: Brain-derived-neurothropic-factor (BDNF) gene

BDNF is a candidate gene for ADHD.⁵¹²⁰

The BDNF gene is involved in the formation of the dopamine D3 receptor (see OMIM on DRD3) in the nucleus accumbens during development and adolescence.
In children with ADHD, poorer performance on the Stroop test of executive function correlated BDNF GG genotype rs2030324.²²⁹ One study found a positive correlation between BDNF gene polymorphism rs10835210 and ADHD-HI and a negative correlation of BDNF-rs12291186 with one or both mutant alleles with ADHD.²³⁰

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.⁵²³¹

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

OMIM: NERVE GROWTH FACTOR

Source¹²⁰

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

OMIM: GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR; GDNF

Source¹²⁰

1.54. UNC5, C. ELEGANS, HOMOLOG OF, B; UNC5B (chromosome 10q22.1)¶

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

OMIM: UNC5, C. ELEGANS, HOMOLOG OF, B; UNC5B

• SNP: rs16928529 position: 72652991; In intron of UNC5B¹²⁰
  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 control of cell growth and division. Glypican 6 is a putative cell surface coreceptor for growth factors, extracellular matrix proteins, proteases and anti-proteases.
Mutations of glypican 6 are associated with omodysplasia 1.

OMIM: GLYPICAN 6; GPC6

• SNP: rs7995215 Position: 93206507; In intron of GPC6¹²⁰
  P: 1.35E-08
  One study found this gene to be one of the 51 most likely gene candidates 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 protein CNTN5 is a member of the immunoglobulin superfamily and the contactin family. Contactins mediate cell surface interactions during nervous system development. CNTN5 is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. CNTN5 may play a role in axon junction formation 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.²³²
CNTN5 is associated with

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

Paralog: CNTN4

One study found CNTN5 (variant rs2515376) to be one of 96 ADHD candidate genes.²

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 part of centrosomes. They play an important role in the formation of the basal body and cilia. POC1B plays an important role in centrioles formation and/or stability and cilia genesis. POC1B is involved in early steps of centriole duplication as well as in the later steps of centriole length control. POC1B acts in concert with POC1A to ensure centriole integrity and proper mitotic spindle formation. POC1B is required for primary cilia formation, cilia length, and also cell proliferation. POC1B is required for the integrity of the retina.²³³
POC1B is associated with

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

Related Signal Paths:

• Ciliopathies

Paralog: POC1A

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁴³

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 protein CTNNA2 enables actin filament binding activity. It is involved in the following functions:

• Inhibition of Arp2/3 complex-mediated actin nucleation and Arp2/3-mediated actin polymerization Thus, CTNNA2 suppresses excessive actin branching that would affect neurite growth and stability.²³⁴
• Regulation of neuron migration / development of the nervous system
• Regulation of the development of neuron projections
• 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 morphological plasticity of synapses and lamination of cerebellum and hippocampus during development.
• Control of the startle modulation.

CTNNA2 is involved in the following disorders:

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

OMIM: CATENIN, ALPHA-2

• SNP: rs13395022 position: 79735768; In intron of CTNNA2¹²⁰
  p: 9.68E-06

Circadian rhythm¶

The circadian clock, an internal timekeeping system, regulates various physiological processes by generating approximately 24-hour circadian rhythms in gene expression that translate into rhythms in metabolism and behavior. The circadian system is an important regulator of a variety of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immunological, cardiovascular, and renal functions. The circadian system consists of two major components: the central clock, located in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks, found in almost all tissues and organ systems. Both the central and peripheral clocks can be reset by environmental stimuli, also called zeitgebers. The predominant zeitgeber for the central clock is light, which is perceived by the retina and transmitted directly to the SCN. The central clock controls the peripheral clocks through neural and hormonal signals, body temperature, and feeding-related signals, so that all clocks are tuned to 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 to reach a peak in protein expression every 24 hours to control when a particular physiological process is most active in relation to the solar day. Transcription and translation of key clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1, and CRY2) plays a critical role in rhythm formation, while delays due to post-translational modifications (PTM) are important in determining the period (tau) of rhythms (tau refers to the period of a rhythm and is the temporal length of a complete cycle). A diurnal rhythm is synchronized with the day-night cycle, whereas ultradian and infradian rhythms have periods shorter and longer than 24 hours, respectively. Disturbances in circadian rhythms contribute to the pathology of cardiovascular disease, cancer, metabolic syndromes, and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular mechanism of the circadian clock. The transcription factors CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2 form the positive link of the feedback loop, acting in the form of a heterodimer and activating the transcription of nuclear clock genes and clock-controlled genes (involved in important metabolic processes) carrying E-box elements (5’-CACGTG-3’) in their promoters. The major clock genes: PER1/2/3 and CRY1/2, which are transcriptional repressors, form the negative limb 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 nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and activate and repress ARNTL/BMAL1 transcription, respectively.²³⁵

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 Locomoter Output Cycles Kaput Protein; Clock (Mouse) Homolog; Clock Homolog (Mouse); EC 2.3.1.48’); Clock Homolog; BHLHE8; HCLOCK

The protein CLOCK plays a central role in the regulation of circadian rhythms. CLOCK encodes a transcription factor of the bHLH (basic helix-loop-helix) family and has DNA-binding histone acetyltransferase activity. CLOCK forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of period (PER1, PER2, PER3) and cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting with CLOCK/ARNTL complexes in a feedback loop. CLOCK regulates 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 circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10, and genes involved in glucose and lipid metabolism. CLOCK promotes rhythmic opening of chromatin and regulates DNA accessibility of other transcription factors. The CLOCK-ARNTL2/BMAL2 heterodimer activates 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.²³⁶
CLOCK is associated with

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

Paralog: NPAS2

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

CLOCK is a candidate gene for ADHD.⁵
The AA and AG gene variants of rs1801260 correlated significantly with ADHD. Similarly, Rs1801260 polymorphism is a risk factor for ADHD.²³⁷ Increased expression of CLOCK, PER1, lncRNA HULC, and lncRNA UCA1 correlated with
evening chronotype, problems falling asleep and staying asleep, disturbances of the sleep-wake transition, and excessive sleepiness in ADHD. There was no significant association between individual genes and specific sleep parameters.²³⁸

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. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior.
PER1 is upregulated by CLOCK/ARNTL heterodimers, but then represses this upregulation in a feedback loop by PER/CRY heterodimers interacting with CLOCK/ARNTL. PER1 is a transcriptional repressor that forms a core component of the circadian clock.
PER1 regulates the expression of circadian target genes at the posttranscriptional level but may not be required for repression at the transcriptional level. PER1 controls PER2 protein decay. PER1 represses CRY2, preventing its repression of CLOCK/ARNTL target genes such as FXYD5 and SCNN1A in the kidney and PPARA in the liver. In addition to its involvement in the maintenance of the circadian clock, PER1 has an important function in the regulation of various processes. PER1 is involved in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR with glucocorticoid response elements (GREs) through ARNTL:CLOCK. PER1 plays a role in modulating the neuroinflammatory state by regulating the release of inflammatory mediators, such as CCL2 and IL6. In spinal astrocytes, PER1 inhibits the MAPK14/p38 and MAPK8/JNK-MAPK cascades and subsequent activation of NFkappaB. PER1 coordinately regulates the expression of several genes involved in the regulation of renal sodium reabsorption. PER1 can act as an activator of gene expression in a gene- and tissue-specific manner; in the kidney, PER1 increases the expression of WNK1 and SLC12A3 in cooperation with CLOCK. PER1 modulates the hair follicle cycle. PER1 represses (suppresses) CLOCK-ARNTL/BMAL1-induced transcription of BHLHE40/DEC1.²³⁵
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 was reported to correlate with general ADHD symptoms.¹⁵ Increased expression of CLOCK, PER1, lncRNA HULC and lncRNA UCA1 correlated with
evening chronotype, problems falling asleep and staying asleep, disturbances of the sleep-wake transition, and excessive sleepiness in ADHD. There was no significant association between individual genes and specific sleep parameters.²³⁸

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

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

The PER2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.017.⁶

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 neuronal signal of the gut with antimicrobial and metabolic responses. This signal is controlled by innate lymphoid cells type 3 (ILC3). Food intake rapidly activates a population of intestinal neurons that produce VIP. Projections of VIP-producing neurons in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIPR2. VIPR2 inhibits IL22 synthesis. This has the effect of reducing the level of epithelial cell-derived antimicrobial peptides while increasing the expression of lipid-binding proteins and transporters. Thus, during food consumption, activation of VIP-producing neurons promotes the growth of segmented filamentous bacteria associated with the epithelium and increases lipid absorption. This establishes a nutrition- and circadian-regulated dynamic neuroimmune circuit in the gut that moderatesz between IL22-mediated innate immune protection and nutrient absorption efficiency.

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

Vipr2 -/- mice (VPR2-KO mice) are unable to maintain normal resting/activity circadian rhythms and show no circadian expression of the central clock genes Per1 (602260), Per2 (603426), and Cry1 (601933) and of the clock-controlled gene encoding arginine vasopressin (AVP; 192340) in the suprachiasmatic nuclei. In addition, VPR2-KO mice showed no acute induction of Per1 and Per2 by nocturnal illumination.

OMIM: VASOACTIVE INTESTINAL PEPTIDE RECEPTOR 2; VIPR2

Source⁴⁷

1.79. KAT2B, LYSINE ACETYLTRANSFERASE 2B¶

The protein KAT2B (lysine acetyltransferase 2B) is involved in²³⁹

• Apoptotic pathway signaling in synovial fibroblasts
• Signaling pathway of regulation of activated PAH-2p34 by proteasome-mediated degradation
• Protein kinase binding
• KAT2B is a histone acetyltransferase (HAT) and thus increases transcriptional coactivator activity
• Has significant histone acetyltransferase activity with nuclear histones (H3 and H4) and also 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 mitogenic activity of the adenoviral oncoprotein E1A
• Acts as a circadian transcriptional coactivator, enhancing the activity of circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers
• Acetylation of TBX5, thereby participating in heart and limb development
  • Acetylation regulates nucleocytoplasmic shuttling of TBX5
• inhibits centrosome amplification by mediating acetylation of PLK4
• Acetylates RRP9/U3-55K, a key subunit of the U3 snoRNP complex, impairing pre-rRNA processing
• Acetylates MAPRE1/EB1 to promote dynamic kinetochore-microtubule interactions in early mitosis
• Acetylated spermidine
• is recruited by the viral protein Tat upon HIV-1 infection. Regulates the transactivating activity of Tat and may help induce chromatin remodeling of proviral genes.

KAT2B is associated with disease:

• Holt-Oram syndrome
• spinocerebellar ataxia 7

OMIM: KAT2B, LYSINE ACETYLTRANSFERASE 2B

KAT2B is a candidate gene for ADHD.²⁴⁰

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

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 protein CADM1 enables signal receptor binding activity. CADM1 is involved in:²⁴¹

• Cell recognition
• positive regulation of cytokine production
• promotes the cytotoxicity of natural killer (NK) cells
• promotes the secretion of interferon-gamma (IFN-gamma)
• Organization of cell adhesion (cell connections).
• relevant 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 formation
• May be involved in neuronal migration, axon growth, pathfinding, and fasciculation on axons of differentiating neurons
• is located in the plasma membrane
• is used for 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 glia and neurons. In astrocytes, SynCAM1 is functionally linked to erbB4 receptors, which are involved in the control of both neuronal/glial development and mature neuronal and glial function.²⁴²

CADM1 is associated with:

• Cervix Uteri Carcinoma In Situ
• Retroperitoneal Fibrosis

OMIM: CADM1, CELL ADHESION MOLECULE 1

The CADM1 rs10891819 genotype (T alleles) correlated negatively with defects in the Stroop test in one study, thus positive with inhibitory ability and therefore ADHD-protective.²⁴³ Knockdown of CADM1 in astrocytes in mice causes ADHD symptoms. The mice also showed daytime (during the light period of the light cycle), suggesting that their diurnal pattern of locomotor and/or sleep activity was impaired. The mice further showed consistent aimless exploratory behavior in familiar surroundings, as well as increased impulsivity and aggeressiveness (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).²⁴²

Immune system¶

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

The protein CSMD2 appears to be involved in the control of the complement cascade of the immune system. It may serve as a tumor suppressor for colorectal cancer. Gene defects are associated with schizophrenia.

OMIM: CUB AND SUSHI MULTIPLE DOMAINS 2

• SNP: rs2281597 position: 34132445; In intron of CSMD2¹²⁰
  p: 5.41E-07
  One study found this gene to be one of the 51 most likely gene candidates 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, a B-box type 1 and a B-box type 2, and 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 antiviral response downstream of various DNA-encoded pattern recognition receptors (PRRs). TRIM26 promotes IRF3 nuclear ubiquitination and proteasomal degradation. TRIM26 links TBK1 and NEMO during the innate response to viral infection, leading to activation of TBK1.

TRIM26 is associated with neural tube defects.

One study found this gene to be one of the 51 most likely gene candidates 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 protein MYO1G 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 required during the immune response for recognition of rare antigen-presenting cells by regulating T cell migration. Unconventional myosins are actin-based motor molecules with ATPase activity and serve intracellular movement.
MYO1G acts as a regulator of T cell migration by generating membrane tension that forces cellular meandering search, thereby enhancing recognition of rare antigens during lymph node surveillance, enabling pathogen eradication. MYO1G is also required in B cells, where it regulates various membrane/cytoskeleton-dependent processes. MYO1G is involved in phagocytosis with the Fc-gamma receptor.
MYO1G forms the minor histocompatibility antigen HA-2. More generally, minor histocompatibility antigens (mHags) are immunogenic peptides that, when complexed with MHC, can elicit an immune response upon recognition by specific T cells. The peptides are derived from polymorphic intracellular proteins that are cleaved by the normal pathways of antigen processing. 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) after hematopoietic stem cell transplantation from HLA-identical sibling donors.²⁴⁴
MYO1G is associated with

• Graft-versus-host disease. This is a common complication after bone marrow transplantation (BMT) due to mismatch of minor histocompatibility antigen in HLA-identical sibling marrow grafts.

Paralog: MYO1D

One study found MYO1G (variant rs6958168) to be one of 96 ADHD candidate genes.²

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 protein TLR4 belongs to the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs generally exist as homodimers (heterodimers have been reported) and are located on immune cells, macrophages, B lymphocytes, and mast cells. TLRs are highly conserved from Drosophila to humans and share 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. Different TLRs exhibit different expression patterns. In silico studies have revealed particularly strong binding of surface TLR4 to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of 2019 coronavirus disease (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 through MYD88, TIRAP and TRAF6 to activate NF-kappa-B, cytokine secretion and inflammatory response. TLR4 is involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). The responses triggered by Ni(2+) require non-conserved histidines and are therefore species-specific. Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act through 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 first signal is triggered by binding of oxLDL or amyloid-beta 42 to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers an inflammatory response leading to NF-kappa-B-dependent production of cytokines CXCL1, CXCL2, and CCL9 via the MYD88 pathway and cytokine CCL5 via the TICAM1 pathway and secretion of IL1B. TLR4 binds electronegative LDL (LDL(-)) and mediates LDL(-)-induced cytokine release. Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces activation of p38 MAPK and ERK1/2 mainly via TLR2, but also partially via the TLR4 receptor. TLR4 is activated by the signaling pathway regulator NMI, which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, thereby promoting activation of the nuclear factor NF-kappa-B.²⁴⁵
TLR4 is associated with

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

Paralog: TLR7

One study found TLR4 (variant rs10121605) to be one of 96 ADHD candidate genes.²

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 causes increased GRβ expression²⁴⁶ and has been associated with ADHD.²⁴⁷ However, the GRβ variant does not bind cortisol, is transcriptionally inactive, and is considered a dominant-negative inhibitor of the functional GRα variant.²⁴⁸
The GR-9β-stabilizing polymorphism has been associated with increased ACTH and cortisol stress responses.²⁴⁹

The combined inhibitory effect of the GR-9β haplotype and stress load may reduce GR activity to pathologically low levels, contributing to ADHD-related behavior. The GR-9β haplotype of the glucocorticoid receptor gene NR3C1 is associated with increased ADHD risk. In carriers of this haplotype, stress exposure and ADHD severity correlate more strongly than in noncarriers. This gene-environment interaction was further enhanced when affected individuals were also carriers of the homozygous 5-HTTLPR L allele rather than the S allele.²⁵⁰

In contrast, the Bcll GG haplotype of GR showed a flattened cortisol stress response in males and a greatly increased cortisol stress response in females (although the subjects were all using hormonal contraception)²⁴⁹

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

OMIM: FK506-BINDING PROTEIN 5; FKBP5

The FKBP5 gene modulates glucocorticoid receptor sensitivity.
In terms of damage from long-term exposure to stress, there is a significant difference whether stress occurs during the developmental phase of the brain or in adulthood. Downregulation in adulthood has fewer long-term consequences. Epigenetic demethylation of the FKBP5 gene, which modulates glucocorticoid receptor sensitivity,²⁵¹ is mediated by stress only during the differentiation and proliferation phase of neurons (i.e., childhood and adolescence), but no longer in mature neurons (i.e., adults).²⁵²

The FKBP5 gene polymorphisms rs1360780, rs4713916, and rs3800737 cause increased FKBP51 concentrations in the blood and thus an enhanced cortisol response to psychosocial stress. HPA axis re-regulation is slowed and remains incomplete for prolonged periods, even with repeated stress exposure. In contrast, the FKBP5 gene polymorphism Bcl1 shows an anticipatory cortisol response to psychosocial stress.²⁵³

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

The CDH23 gene encodes a member of the cadherin superfamily, which includes calcium-dependent cell-cell adhesion glycoproteins.
CDH23 is associated with adenomas of the pituitary gland (second stage of the HPA axis). Pituitary adenomas have a prevalence of 14 to 22%.²⁵⁴

OMIM: CADHERIN 23

The CDH23 SNP rs11594082 position: 72969259; In intron of CDH23 is a candodata gene for ADHD.¹²⁰
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 protein NAT2 is an enzyme responsible for the activation and deactivation of arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations divide into fast, intermediate, and slow acetylator phenotypes. NAT2 is involved in the detoxification of a variety of hydrazine and arylamine drugs. NAT2 catalyzes the N- or O-acetylation of several arylamine and heterocyclic amine substrates and is capable of bioactivating several known carcinogens.

NAT2 is associated with

• Acetylation, slow
  • NAT2 acetylates, among others,²⁵⁵
    • Sulfanilamide
    • Chloramphenicol
    • Glucocorticoids
• multiple chemical sensitivity
• Cancer
• Drug toxicity

Related metabolic pathways:

• Caffeine Trail
• Pharmacokinetics
• Paracetamol-ADME

Paralog: NAT1

One study found NAT2 (variant rs12676224) to be one of 96 ADHD candidate genes.²
The NAT2 genotypes rr and rs are phenotypically fast excretors. Drugs that have to be acetylated for excretion (e.g. glucocorticoids) are often ineffective or resistant to therapy in rapid excretors, while slow excretors often experience adverse effects.²⁵⁵ Because glucocorticoids are required to reshut down the HPA axis after a stress response, we think it is conceivable that NAT2-rr and -rs carriers may be at higher risk for HPA axis shutdown problems, which (as evident from the ADHD model of SHR) may lead to ADHD-C symptomatology.

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 protein DUSP6 belongs to the dual specificity subfamily of protein phosphatases. These phosphatases inactivate their target kinases by dephosphorylation of both phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the superfamily of mitogen-activated protein kinases (MAPK/ERK, SAPK/JNK, p38) associated with cell proliferation and differentiation. Different members of the dual-specificity phosphatase family exhibit different substrate specificities for different MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli.
DUSP6 inactivates MAP kinases, especially ERK2. DUSP6 is expressed in many tissues, especially in heart and pancreas. DUSP6, unlike most other members of this family, is localized in the cytoplasm.
DUSP6 plays an important role in the relief of chronic postoperative pain. DUSP6 is necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, resulting in the resolution of acute postoperative allodynia. DUSP6 is important for 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 AP1 transcription factor expression.²⁵⁶
DUSP6 is associated with

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

Related signaling pathways:

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

Paralog: DUSP7

A study on 6-hydroxydopamine (6-OHDA)-induced PC12 cells and rats found that dioscin could help against Parkinson’s disease because it could

• drastically improved the viability of the cells
• reduced the level of reactive oxygen species (ROS)
• improved the motor behavior
• Tyrosine hydroxylase (TH) levels increased
• restored the levels of glutathione (GSH) and malondialdehyde (MDA) in rats.
  Possible mechanisms of diospin action included an increase in DUSP6 expression level (by 1.87-fold in cells and 2.56-fold in rats) and regulation of DUSP6 that adjusted Keap1/Nrf2 signaling. Dioscin protected against oxidative stress via DUSP6 signaling.²⁵⁷

MAPK phosphatase MKP3/DUSP6 is an inhibitor mitogen-activated protein kinase (MAPK) and prevents depolarization-dependent release of dopamine in rat PC12 cells²⁵⁸

DUSP6 was identified as an ADHD candidate gene in a large GWAS.¹⁴³

Other stress consequences¶

1.108. NCL, nucleolin¶

Other names: Nsr1, C23, Protein C23

NCL is the major eukaryotic nucleolar phosphoprotein and is involved in ribosome synthesis and maturation. It is mainly located 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 to be involved in the process of transcription elongation. NCL is involved in an astonishing number of molecular processes NCL interacts with many types of molecules and regulates many facets of DNA and RNA metabolism.

Nucleolin (and ELAVL1) act independently with MBII-52 snoRNA by co-immunoprecipitation.
snoRNAs are small nucleolar RNAs and are among the most abundant non-coding RNA species in all organisms. They are required for the maturation of preribosomal 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.” In contrast to canonical snoRNAs that target snRNAs or rRNAs, the orphan snoRNA MBII-52 has 18 nucleotides of complementarity to the pre-mRNA of the serotonin 2C receptor, thereby reducing its mRNA expression.²⁵⁹

NCL²⁶⁰

• is a histone chaperone and a chromatin remodeler involved in DNA repair, replication and recombination.
• is involved in the transcription and maturation of ribosomal RNA and in the assembly and transport of ribosomes.
• is involved in transcription, splicing, stability, transport, and translation of many mRNA.
• contributes in the cytosol to the anchoring of microtubules to centrosomes in interphase cells and to microtubule polymerization.
• regulates Ras protein assembly and interaction as well as MAPK signal transduction at the plasma membrane.
• acts on the cell surface as a co-receptor for cytokines, growth factors and matrix proteins
• is subsequently involved in numerous pathologies.
• involved in²⁶¹
  • Cell proliferation
  • Angiogenesis
  • Apoptosis regulation
  • Stress response
  • microRNA processing

NCL is associated with

• Childhood ependymoma
• Spinal muscular atrophy
• Cancer
• Viral diseases
• neurodegenerative diseases

Stress conditions such as heat shock, γ-irradiation, and camptothecin administrationcan cause a dramatic redistribution of NCL from the nucleolus to the nucleoplasm in a p53-dependent manner. This may transiently 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. After stress stimulation, NCL may undergo specific posttranslational modification, such as serine phosphorylation by casein kinase II, which promotes the interaction of NCL with RPA (replication protein A), and accumulation in the nucleoplasm occurs because the nucleoplasm contains a large amount of RPA. This redistribution is associated with increased formation of the NCLRPA complex, which further prevents initiation and elongation during DNA replication.

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰
Another study found NCL (variant rs16828074) to be the most likely of 96 candidate genes.²

Broadly effective mechanisms¶

Transcription¶

1.95. RERE¶

The RERE protein is critical for normal development before birth. RERE dysfunction likely alters the activity of many genes involved in pre-birth development. These changes prevent normal development of tissues in the brain, eyes, heart, and other organs. The RERE protein interacts with other proteins called transcription factors that control the activity (transcription) of certain genes. The RERE protein helps ensure that these transcription factors turn on (activate) and turn off (repress) a number of genes that are important for early development, ensuring that genes are activated (expressed) at the right time and place for proper tissue formation. Research suggests that the RERE protein plays a role in brain, eye, inner ear, heart and kidney development.²⁶²

One study found RERE to be 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 affects cell proliferation and differentiation in embryogenesis. HES1 regulates its own expression via a negative feedback loop and oscillates with a periodicity 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 = 0.016.⁶

1.86. FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1¶

The protein FEZF1 is a transcriptional repressor. In mice, FEZF1 is expressed in the forebrain during early embryonic development.
FEZF1 represses the transcription factor HES5, which contributes to the control of neural stem cell differentiation. FEZF1 helps divide the caudal forebrain into three distinct parts during development prethalamus, thalamus and pretectum: FEZF1-KO mice have no prethalamus and a smaller thalamus.
A loss-of-function mutation in FEZF1 causes Kallmann syndrome.
As axons develop and migrate in the early embryo, FEZF1 enables olfactory neuron axons to connect to the central nervous system in the mouse model. During neuronal development, GnRH neurons migrate through one of these olfactory axon pathways, and loss of function of FEZF1 therefore leads to loss of GnRH neurons in the brain, the hallmark of Kallmann syndrome.²⁶³

OMIM: FEZF1, FEZ FAMILY ZINC FINGER PROTEIN 1

FEZF1 is a candidate gene for ADHD.²⁶⁴

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, 250kDa, Transcription Initiation Factor TFIID Subunit 1, TBP-Associated Factor 250 KDa, Cell Cycle Gene 1 Protein, EC 2.7.11.1, TAF(II)250

The TAF1 protein:

• is the largest subunit and the core scaffold of the basal transcription factor complex TFIID.
• contains novel 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
• shows histone acetyltransferase activity towards histones H3 and H4
• binds to core promoter sequences comprising the transcription start site
• binds to activators and other transcriptional regulators, affecting the rate of transcription initiation
• contains two independent protein kinase domains at the N- and C-terminus
• possesses acetyltransferase activity
• may act as a ubiquitin-activating/conjugating enzyme.
• controls apoptotic pathways in synovial fibroblasts

Mutations of TAF1 lead to

• Dystonia 3, torsion, X-linked, a dystonia-parkinsonism disorder
• Intellectual development disorder, X-linked, syndrome 33

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

For TAF1, one study found an alteration in expression in ADHD.¹

1.143. ZNF763, Zinc Finger Protein 763¶

Other NAmen: ZNF440L, Zinc Finger Protein 440 Like, DNA-Binding Protein, ZNF

The protein ZNF763 is likely to be involved in transcriptional regulation through RNA polymerase II. ZNF763 appears to have 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.²⁶⁵

ZNF763 is a candidate gene for ADHD.¹⁷⁹

1.134. ZNF615, Zinc Finger Protein 615¶

Other name: FLJ33710

The protein ZNF615 facilitates DNA-binding transcription activator activity, 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 probably active in the nucleus.²⁶⁶

One study found this gene to be one of the 51 most likely gene candidates 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 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 protein POLR1H is a DNA-directed RNA polymerase I subunit. This may play a role in regulating 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.²⁶⁷ RNA polymerase (Pol) I produces ribosomal (r)RNA, an essential component of the cellular protein synthesis machinery that drives cell growth and underlies many basic cellular processes. Transcription by Pol I is subject to a number of intricate control 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.²⁶⁸
POLR1H is associated with

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

OMIM: ZNRD1, ZINC RIBBON DOMAIN-CONTAINING PROTEIN 1

One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

Receptor activity¶

1.41. ARRB2, arrestin beta 2 gene (chromosome 17p13.2)¶

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

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

OMIM: Arrestin beta 2 gene, ARRB2

The ARRB2 gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.004.⁶

Neurotransmitter storage¶

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

Synaptophysin is found in synaptic vesicles of neurons in brain, spinal cord, and retina, and in similar vesicles in adrenal medulla and motor endplate.
The function of synaptophysin is poorly understood. It appears to form a channel in the membrane of neurons, allowing the uptake of neurotransmitters from the cytosol into the synaptic vesicles.

OMIM: SYNAPTOPHYSIN; SYP

The SYP gene was identified as a candidate gene for ADHD in a 2006 study with p = 0.045.⁶

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 protein NT5C2 is a hydrolase and a cytosolic 5’-nucleotidase with broad specificity. NT5C2 plays an important role in cellular purine metabolism. NT5C2 mainly acts on inosine 5’-monophosphate and other purine nucleotides. NT5C2 catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5’-monophosphates. NT5C2 possesses phosphotransferase activity by which it can transfer a phosphate from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine, and guanosine.²⁶⁹

NT5C2 is associated with

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

One study found this gene to be one of the 51 most likely gene candidates 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 protein PCDH7 st an integral membrane protein that appears to play a role in cell-cell recognition and adhesion and that has an extracellular domain containing 7 cadherin repeats.²⁷⁰
PCDH7 expression increases during cocaine withdrawal.²⁷¹
PCDH7 is associated with

• Astigmatism
• Epilepsy, myoclonic juvenility

Related signaling pathways:

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

Paralog: PCDH1

This gene was identified as an ADHD candidate gene in a large GWAS.¹⁴³

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 protein SPATA13 facilitates guanyl nucleotide exchange factor activity for the GTPases RHOA, RAC1, and CDC42 and identical protein binding activity. SPATA13 is involved in cell migration, formation of cell processes bound to the plasma membrane, regulation of cell migration, and adhesion formation and degradation through a mechanism dependent on RAC1, PI3K, RHOA, and AKT1. SPATA13 increases both RAC1 and CDC42 activity, but decreases the amount of active RHOA. SPATA13 is required for the upregulation of MMP9 via the JNK pathway in colorectal tumor cells. SPATA13 is involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression. SPATA13 is found in several cellular components, including filopodium, lamellipodium, and curl membrane.²⁷²
SPATA13 is associated with

• Optical atrophy 3, autosomal dominant
• Dravet syndrome

OMIM: SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13

• SNP: rs17079773 Position: 23496384; In intron of SPATA13 ¹²⁰
  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 and consist of an alpha chain and a beta chain. As transmembrane proteins, they cross the cell membrane, in which they are firmly anchored. They form an important function in cell signal transduction. They connect individual cells with each other and cells with the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
ITGAE is a receptor for E-cadherin. It binds integrin beta 7 (β7- ITGB7) to form the complete heterodimeric integrin molecule αEβ7. ITGAE mediates adhesion of intra-epithelial 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 beta-7 integrin, this protein forms the E-cadherin-binding integrin known as human mucosal lymphocyte-1 antigen. ITGAE is preferentially expressed in human intestinal intraepithelial lymphocytes (IEL) and, in addition to its role in adhesion, may also serve as an accessory molecule for IEL activation.²⁷³
ITGAE is associated with

• Enteropathy-associated T-cell lymphoma
• Mycosis Fungoides

Related Signal Paths:

• Autophagy signaling pathway
• Dendritic Cells Developmental Lineage Pathway

Paralog: ITGA11.

OMIM: INTEGRIN, ALPHA-E

• SNP: rs220470 position: 3611724; In intron of ITGAE¹²⁰
  P: 1.34E-07
  One study found this gene to be one of the 51 most likely gene candidates 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 and consist of an alpha chain and a beta chain. As transmembrane proteins, they cross the cell membrane, in which they are firmly anchored. They form an important function in cell signal transduction. They connect individual cells with each other and cells with the extracellular matrix (adhesion). Integrins are therefore also called adhesion molecules.
The protein ITGA11 is an alpha integrin and contains an I domain. ITGA11 is expressed in muscle tissue and dimerizes with beta-1 integrin in vitro, appearing to bind collagen. Integrin alpha-11/beta-1 is a collagen receptor. Therefore, ITGA11 may be involved in binding muscle tissue to the extracellular matrix.²⁷⁴
ITGA11 is associated with

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

Related Signal Paths:

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

Paralog: ITGA10.

OMIM: INTEGRIN, ALPHA-11

• Rs7164335 66502086 In intron of ITGA11¹²⁰
  p: 1.30E-07
  One study found this gene to be one of the 51 most likely gene candidates for ADHD.¹⁰

Cerebral 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 required for sperm flagellum function. SPAG16 encodes two major proteins associated with the sperm tail axoneme and the postmeiotic germ cell nucleus, respectively. The axoneme is a microtubular backbone composed 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 apical surface of the cell to initiate the subsequent steps of building the central pair apparatus of motile cilia.²⁷⁵
SPAG16 is associated with

• Pulmonary subvalvular stenosis (narrowing of the outflow tract of the right ventricle to the pulmonary artery (pulmonary artery))
• Brain Small Vessel Disease 2
  • Cerebral small vessel disease
  • May lead to cognitive deficits in attention and executive functioning²⁷⁶

Related signaling pathway: protein kinase binding.

SPAG16 was identified as an ADHD candidate gene in a large GWAS.¹⁴³