Evidence for an Association of the Dopamine D5 Receptor Gene on Age at Onset of Attention Deficit Hyperactivity Disorder

Lasky‐Su, Jessica; Biederman, Joseph; Laird, Nan M.; Tsuang, Ming T.; Doyle, Alysa E.; Smoller, Jordan W.; Lange, Christoph; Faraone, Stephen V.

doi:10.1111/j.1469-1809.2007.00366.x

Cited by 15 publications

(11 citation statements)

References 52 publications

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“…Nonetheless, only a few studies have tested for associations between DRD5 and ADHD beyond this repeat (Hawi et al 2003;Lasky-Su et al 2007b), perhaps due to the diYculty of genotyping polymorphisms that lie within the gene itself, rather than in adjoining pseudogenes (Housley et al 2009). The results of the present and previous meta-analyses strongly support association between DRD5 and ADHD, thus additional studies are needed to further explore this relation and attempt to identify the functional polymorphism(s) within the gene that underlie this association.…”

Section: Dopamine D5 Receptor Gene (Drd5)mentioning

confidence: 97%

Candidate gene studies of ADHD: a meta-analytic review

2009

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Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.

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Section: Dopamine D5 Receptor Gene (Drd5)mentioning

confidence: 97%

Candidate gene studies of ADHD: a meta-analytic review

2009

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“…Earlier work of the authors had suggested that environmental exposure outside the womb were less likely to contribute significantly to the development of ADHD with a very early age of onset (Lasky-Su et al 2007). The number of children included in the analysis was 930 with a mean age of 10.86 years, 810 of them being males.…”

Section: Reviewmentioning

confidence: 99%

Genome-wide association studies in ADHD

2009

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Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent–child trio’s collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the ‘classic’ ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence—as yet—points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of ‘new’ neurotransmission and cell–cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important.

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“…We performed the analyses under the null hypotheses of "no association in the presence of linkage" for the recessive model. We selected the recessive model based on the results from previous linkage studies of ASD (45) and the recommendations in the literature (46). Rejecting the null hypothesis of no association suggests an actual allelic association that goes far beyond the weaker conclusion of linkage.…”

Section: Statistical Analysesmentioning

confidence: 99%