Child and Adolescent Psychiatric Clinics of North America
Genetics of Attention Deficit Hyperactivity Disorder
Section snippets
The dopamine D4 receptor
Both noradrenaline and dopamine are potent agonists of DRD4 [19], and the D4 receptor is prevalent in frontal-subcortical networks implicated in the pathophysiology of ADHD by neuroimaging and neuropsychologic studies [20]. Researchers have predominantly focused on a tandem repeat polymorphism in exon III of DRD4 because in vitro studies have shown that one variant (the 7-repeat allele) produces a blunted response to dopamine [21], [22]. Faraone and colleagues [4] conducted a meta-analysis of
Noradrenergic receptors: alpha-2A adrenergic receptor, 2C, and 1C
Three adrenergic receptors have been examined in ADHD. The alpha-2A adrenergic receptor (ADRA2A) has a promoter-region SNP (-1291 C > G) that has been examined in both case-control and family-based studies. Comings and colleagues [91] reported an association between genotypes at this SNP and ADHD symptom scores and that the G-1291C allele was associated with ADHD and oppositional defiant or conduct disorder symptoms, whereas the C-1291G allele was associated with a spectrum of other conditions,
Serotonin receptors: HTR1B and HTR2A
Of the family-based association studies of a silent SNP (861G > C) in the gene coding for the serotonin HTR1B receptor [108], [110], [111], [112], [113], [114], only the multisite study by Hawi and colleagues [110] reached statistical significance, suggesting overtransmission of the G861C allele. Smoller and colleagues pooled data from [110], [111], [112] and identified statistically significant overtransmission of this allele (OR = 1.35; CI, 1.13–1.62, P = .009) that strongly suggested
Synaptasomal-associated protein of 25kD
SNAP25 is a 206 amino acid protein found on chromosome 20p12. The gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Its relevance to ADHD was motivated by the coloboma mouse, which has a hemizygous two centimorgan deletion of a segment on chromosome 2q, including the gene-encoding SNAP25. The coloboma mutation leads to spontaneous hyperactivity, delays in achieving complex neonatal motor abilities, deficits in hippocampal physiology
Summary
Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (ie, DBH, MAO-A, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from a neurobiologic systems perspective, but available data are sparse
References (157)
- et al.
Nature, nurture, and attention deficit hyperactivity disorder
Dev Rev
(2000) - et al.
Molecular genetics of attention deficit hyperactivity disorder
Biol Psychiatry
(2005) - et al.
Adoptive and biological families of children and adolescents with ADHD
J Am Acad Child Adolesc Psychiatry
(2000) - et al.
A genomewide scan for loci involved in attention-deficit/hyperactivity disorder
Am J Hum Genet
(2002) - et al.
Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism
Am J Hum Genet
(2002) - et al.
A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q
Am J Hum Genet
(2003) - et al.
Neurobiology of attention-deficit hyperactivity disorder
Biol Psychiatry
(1998) - et al.
Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD
Neurosci Lett
(2005) - et al.
Association between DRD4 gene and performance of children with ADHD in a test of sustained attention
Biol Psychiatry
(2006) - et al.
Joint analysis of DRD5 marker concludes association with ADHD confined to the predominantly inattentive and combined subtypes
Am J Hum Genet
(2004)
Pharmacotherapy of attention deficit hyperactivity disorder
Child Adolesc Psychiatr Clin N Am
Neural development is regulated by classical neurotransmitters: dopamine D2 receptor stimulation enhances neurite outgrowth
Biol Psychiatry
Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype
Biol Psychiatry
Dopamine D2 receptors (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication
Biol Psychiatry
Lack of significant association between -1021C–>T polymorphism in the dopamine beta hydroxylase gene and attention deficit hyperactivity disorder
Neurosci Lett
Dopaminergic system genes in ADHD: toward a biological hypothesis
Neuropsychopharmacology
A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder
Behav Brain Res
Association between Alpha-2a-adrenergic receptor gene and ADHD inattentive type
Biol Psychiatry
The worldwide prevalence of ADHD: is it an American condition?
World Psychiatry
The prevalence and correlates of adult ADHD in the United States: results from the national comorbidity survey replication
Am J Psychiatry
Genetics of hyperactivity
J Child Psychol Psychiatry
The psychiatric status of the legal families of adopted hyperactive children
Arch Gen Psychiatry
Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate
Mol Psychiatry
Pooled genome-wide linkage data on 424 ADHD ASPs suggests genetic heterogeneity and a common risk locus at 5p13
Mol Psychiatry
A genome-wide scan for attention-deficit/hyperactivity disorder in 155 german sib-pairs
Mol Psychiatry
Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results
Nat Genet
Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD)
Hum Mol Genet
A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention deficit hyperactivity disorder
Am J Med Genet B Neuropsychiatr Genet
Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder
Psychiatr Genet
Meta-analysis of association between a Catechol-O-Methyltransferase gene polymorphism and attention deficit hyperactivity disorder
Behav Genet
Epinephrine and norepinephrine act as potent agonists at the recombinant human dopamine D4 receptor
J Neurochem
Multiple dopamine D4 receptor variants in the human population
Nature
Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants
J Neurochem
Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: a longitudinal study from birth to 11 years of age
J Neural Transm
Analysis of polymorphisms in the dopamine Beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children
Indian Pediatr
Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention-deficit/hyperactivity disorder in Chilean families
Am J Med Genet B Neuropsychiatr Genet
Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD)
Mol Psychiatry
Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5
Mol Psychiatry
5′-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder
Am J Med Genet
Lack of association of dopamine D4 receptor gene polymorphisms with ADHD subtypes in a population sample of twins
Am J Med Genet
No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study
BMC Med Genet
Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population
Am J Med Genet B Neuropsychiatr Genet
Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP-616
Am J Med Genet
The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes
Mol Psychiatry
Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms
Mol Psychiatry
Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder
Neuropsychopharmacology
Collaborative analysis of DRD4 and DAT genotypes in population-defined ADHD subtypes
J Child Psychol Psychiatry
Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B
Am J Med Genet B Neuropsychiatr Genet
Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention
Proc Natl Acad Sci USA
The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA)
Mol Psychiatry
Cited by (122)
Psychiatric genomics: brain pathophysiology and genetic factors
2022, Psychiatric GenomicsPrediction of sleep side effects following methylphenidate treatment in ADHD youth
2020, NeuroImage: ClinicalCitation Excerpt :The dopamine transporter gene (DAT1) and the dopamine D4 receptor gene (DRD4) are the most extensively studied (Arnsten, 2011; Froehlich et al., 2010). The alpha-2A adrenergic receptor gene (ADRA2A) and the norepinephrine transporter gene (SLC6A2) have also been the focus of recent studies (Mick and Faraone, 2008). Candidate genetic predictors of MPH side effects have been reported.
Methylphenidate effects in the young brain: friend or foe?
2017, International Journal of Developmental NeuroscienceCitation Excerpt :A higher rate of symptoms in biological relatives, when compared to adopted ones, was also observed in adoption family studies. However, studies with twins show the most compelling data to prove the heritability of the disorder (Faraone et al., 2005; Mick and Faraone, 2008). Faraone and co-workers estimated a mean heritability of 76% after a review of 20 twin studies from Australia, the European Union, Scandinavia, and the United States, giving to ADHD the title of the most heritable psychiatric disorder (Faraone et al., 2005).
Dr. Eric Mick receives or has received grant support from, is or has been a speaker for, or is or has been on the advisory board for the following sources: McNeil Pediatrics and Janssen Pharmaceuticals, Pfizer, Shire, and the National Institute of Mental Health (NIMH). Dr. Stephen V. Faraone receives or has received grant support from, is or has been a speaker for, or is or has been on the advisory board for the following sources: McNeil Pediatrics, Eli Lilly & Company, the NIMH, the National Institute of Child Health and Development, and the National Institute of Neurological Diseases and Stroke.