Genetics
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The Genetics of ADHD

Like all genetic studies, this area is hard to understand and, so far, has little clinical relevance.  I expect that that will change someday when genome-wide gene testing becomes cost-effective.  I think that that is at least a decade away. 

Genetics

Oct. 05 Review: Dopamine D4 and D5 Receptor, Dopamin and Serotonin Transporter and Synaptosomal Protein Gene Polymorphisms:  ADHD is highly heritable. Meta-analyses or pooled data analyses support association between ADHD and polymorphisms in DRD4, DRD5 and SLC6A3 which encode dopamine D4 and D5 receptors and the dopamine transporter, respectively. A weaker body of evidence also supports associations with SNAP-25 (synaptosomal-associated protein, 25 kDa) and SLC6A4 (serotonin transporter). The genetics of attention deficit hyperactivity disorder. Thapar A, et al. Cardiff University, UK . Hum Mol Genet 2005 Oct 15;14 Spec No. 2:R275-82. Ed: There may be dozens of different polymorphisms with each of the affected genes. Some of these may be harmless, and others harmful to varying degrees.

Jan. 05 Review: Four Genes Some Link to Increased ADHD: Dopamine D4 and D5 Receptors, Dopamine and Serotonin Transporters: ADHD is highly heritable but is a complex disorder involving multiple genes. Over 100 studies have examined the genetics of ADHD by linkage or association. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others possibilities include the dopamine D2 and serotonin 2A receptors. All candidate gene give only modest odds ratios for even the best replicated studies. Molecular genetic studies of ADHD: 1991 to 2004. Bobb AJ, Castellanos FX, et al. NIMH. Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):109-25

Alpha-2A Adrenergic Receptor Gene Dral Polymorphisms Linkage: In a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. The DraI polymorphism of ADRA2A is linked to a causative polymorphism. Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Park L, Nigg JT, et al. Michigan State University. Molecular Psychiatry  2 November 2004.

Genetic Polymorphism of Nicotinic Acetylcholine Receptor Alpha 4: Sequence variations in the coding regions and intron/exon junctions of the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Common polymorphisms were used for transmission disequilibrium test (TDT) analyses. A significant association was found for a 5' intron 2 single nucleotide polymorphism and severe inattention problems (P=0.007, effect size=4, 95% CI 1.3-14.1). The location of the polymorphism is compatible with it affecting pre-mRNA stability or splicing. Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems. Todd RD, Lobos EA, Sun LW, Neuman RJ. Mol Psychiatry 2003;8(1):103-8

SNAP-25 May Be Involved: Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/DdeI allelel to ADHD cases (p<.01). Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population. Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M. Mol Psychiatry 2002;7(8):913-7

Three Genetic Abnormalities Dopamine Transporter, Dopamine Beta-Hydroxylase Genes Found: A Trinity College, Dublin, research group confirmed earlier findings that an abnormal dopamine-transporter gene (DAT1) contributes to ADHD. It is involved in action of methylphenidate (Ritalin). They also found polymorphisms in genes for dopamine beta-hydroxylase and dopamine D5-receptor might be involved in cases in ADHD with the latter stronger in non-familial cases. Mol Psychiatry 99;4:192-6. A new methylphenidate is in the works which used only the biologically active chiral mirror-image form and will avoid or decrease some of the side-effects.

Role of Dopamine Genes Minor: A meta-analysis of DRD4 (13 studies, 571 informative meioses) reports the pooled OR 1.41. For DRD5, (five studies, 340 meioses) pooled OR 1.57. Eleven studies of DAT1, (824 meioses) non-significant pooled OR 1.27. Overall, the meta-analyses support the involvement of the dopamine system genes in ADHD liability variation. Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Maher BS, Marazita ML, Ferrell RE, Vanyukov MM. Psychiatr Genet 2002 Dec;12(4):207-15. (Ed: Meta-analysis can sometimes be comparing studies that are vastly different and miss important finding.)

DRD1 Dopamine Receptor Gene Variant May be Involved: A study of 156 family with ADHD children found a much great transmission of haplotype 3 in affected children (p<.008).  Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder. Misener VL, Luca P, Azeke O, Crosbie J, Waldman I, Tannock R, Roberts W, Malone M, Schachar R, Ickowicz A, Kennedy JL, Barr CL.

7R DRD4 Variants Linked to ADHD: The 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene has been linked to both novelty seeking and to ADHD. The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. The authors determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. However, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in their prior population studies). Over 10% of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this was much less than 0.0001.  U Calif, Irvine. High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder. Grady DL, Chi HC, Ding YC, Smith M, Wang E, Schuck S, Flodman P, Spence MA, Swanson JM, Moyzis RK. Mol Psychiatry. 2003 May;8(5):536-45

7R DRD4 Variant Predicts Higher Methylphenidate Dosage Requirement: In a study of 45 ADHD children, ages 7-15, the dose needed to obtain a 10-point improvement on the Conners' Global Index-Parent assessment with DRD4 7R (n=20) was 30 mg (1.00 mg/kg) vs. 20 mg (0.49 mg/kg) without 7R (n=25). CGI-P normalization with 7R was 47 mg (1.70 mg/kg) vs. 31 mg (0.79 mg/kg) without 7R. ADHD symptom normalization at < or =50 mg methylphenidate was achieved in 58% with 7R versus 95% without (each p=0.002). Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. Hamarman S, Fossella J, et al. Brooklyn, New York. J Child Adolesc Psychopharmacol. 2004 Winter;14(4):564-74

DAT-1 and 7R DRD4: Abnormal Dopamine Transporter or D4 Receptor: ADHD is 1.7 to 17% of population with a large majority boys from 2:1 to 9:1 boys. Heritability has been estimated to be very high at 0.75-0.91. Dopamine-transporter (DAT) knockout mice are hyperactive. Variant of DAT1 gene, which inactivates dopamine, was associated with ADHD in 2 studies. Variant of dopamine receptor D4 gene with 7 tandem repeats also associated with ADHD. Symptoms persist at least into early adolescence with higher school failure, more illicit drugs, more anti-social behavior. 70% respond to stimulants. Recommend both ritalyn and dex-amphetamine be tried. Sustained-release not usually better. Pemoline causes mild toxic hepatitis in 2% with 13 cases hepatic failure reported. 6 ADHD deaths with desipramine and 1 with imipramine, therefore use only as backup or if depression or tics although stimulants OK with tics or seizures. 4 deaths with clonidine-Ritalyn combination. NEJM 3/11/99 340:787; 

DRD4.7 and DAT1*9: Genes for dopamine receptor DRD4 and dopamine transporter DAT1 are highly polymorphic. Two alleles of these genes, namely the DRD4.7 and the DAT1*9 are frequently associated to the attention deficit disorder with hyperactivity. In Europe, the allele for DRD4 receptor with four repetitions (DRD4.4) has the highest frequency, with a median of 69%, followed by DRD4.7, with a frequency of 15%. South American indigenous populations have higher frequencies for DRD4.7 (61%) than for DRD4.4 (29%). The ten repetition allele for DAT1 transporter has a high frequency among Europeans (72%) and Amerindians (100%). The allele DAT1*9 is the second most frequent allele. Rev Med Chil. 2003 Feb;131(2):135-43

DRD4 Affects Caudate Volume; DRD4 Affects Prefrontol Gray: The DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. Durston S, Fossella JA, et al. University Medical Center Utrecht, Utrecht, The Netherlands. Mol Psychiatry. 2005 Feb 22

DAT-1 Variant Imparts Greater Susceptibility in Chinese: Six studies of European descendants have found a Dopamine-Transporter variant linked to an increased risk of ADHD. This study found a 190% increased risk from a 10 repeat variant of the DAT-1 gene even though this gene is much more common in Chinese. The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample. Chen CK, Chen SL, Mill J, Huang YS, Lin SK, Curran S, Purcell S, Sham P, Asherson P. Mol Psychiatry. 2003 Apr;8(4):393-6 DAT1 gene has a variable number of tandem repeats type polymorphism (DAT1VNTR) in the 3'-untranslated region of the mRNA, which was also reported to change its gene expression. Genetic polymorphisms of serotonin and dopamine transporters in mental disorders. Ueno S. J Med Invest. 2003 Feb;50(1-2):25-31


Serotonin 5-HT(1B) Receptor Polymorphism Risk Factor: Researchers identified a haplotype block encompassing 5HT1B receptor gene (HTR1B) and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD children. There was an almost significant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (p < .01). There was paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. Association Between the 5HT1B Receptor Gene (HTR1B) and the Inattentive Subtype of ADHD. Smoller JW, et al. Harvard. Biol Psychiatry 2005 Sep 27.

Serotonin 5-HT(2A) Receptor Polymorphism Risk Factor: Chinese genetic study 3230 ADHD teens, 185 parents, and 185 controls. For the ADHD combined subtype, the T102T genotype is a protective factor and the T102C genotype is a risk factor. For the girl with ADHD combined subtype, the allele C102 is a disease-predisposing gene. Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children. Li J, Wang Y, Qian Q, Wang B, Zhou R. Zhonghua Yi Xue Za Zhi 2002 Sep 10;82(17):1173-6

Serotonin Transporter Gene Polymorphism May be Involved: Reduced central serotonergic activity has been implicated in poor impulse regulation and aggressive behavior in animals, adults and also young children.(1,2) This is third published studies have implicated variation at a polymorphism in the promoter of the serotonin transporter (5HTT; hSERT) in influencing susceptibility to ADHD. Birmingham, UK. Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Kent L, Doerry U, Hardy E, Parmar R, Gingell K, Hawi Z, Kirley A, Lowe N, Fitzgerald M, Gill M, Craddock N. Mol Psychiatry 2002;7(8):908-12

Tyrosine Phosphatase ACP1 SNP Involved in ADHD, CD, and MDD: Protein tyrosine phosphatases have been implicated in the regulation of serotonergic and dopaminergic activity in the central nervous system. NonA/nonA homozygosity at the locus codifying for the low molecular weight protein tyrosine phosphatase (ACP1) is associated with increased rates of major depression in males (P<0.00003), suggesting that the ACP1*A single nucleotide polymorphism (SNP) may be an important marker for psychopathology. This study screened the ACP1*A SNP in 539 controls and 184 male Tourette syndrome (TS) cases, all Caucasians of European descent. The frequency of the nonA allele was markedly increased in TS cases relative to controls (P<0.0005), but this difference was restricted to cases with comorbid attention-deficit hyperactivity disorder (P<0.0001) and conduct disorder (P<0.0002), while having little relevance to TS itself. Neurosci Lett 2002 Sep 20;330(2):198-200