Molecular Genetics of Attention-Deficit/Hyperactivity Disorder

Gene-environment interaction research in psychiatry is new, and is a natural ally of neuroscience. Mental disorders have known environmental causes, but there is heterogeneity in the response to each causal factor, which gene-environment findings attribute to genetic differences at the DNA sequence level. Such findings come from epidemiology, an ideal branch of science for showing that a gene-environment interactions exist in nature and affect a significant fraction of disease cases. The complementary discipline of epidemiology, experimental neuroscience, fuels gene-environment hypotheses and investigates underlying neural mechanisms. This article discusses opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene-environment interactions.

Gene–environment interactions in psychiatry: joining forces with neuroscience

Molecular genetics of attention deficit hyperactivity disorder.

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.

Candidate gene studies of ADHD: a meta-analytic review.

Attention-deficit-hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that impairs social, academic, and occupational functioning in children, adolescents, and adults. In patients with ADHD, neurobiologic research has shown a lack of connectivity in key brain regions, inhibitory control deficits, delayed brain maturation, and noradrenergic and dopaminergic dysfunction in multiple brain regions. The prevalence of this disorder in the United States is 6–9% in youth (i.e., children and adolescents) and 3–5% in adults. Prevalence rates for youth are similar worldwide. Children with ADHD are at greater risk than children without ADHD for substance abuse and delinquency whether or not they receive drug therapy; however, early treatment with psychoeducation as well as drug therapy and/or behavioral intervention may decrease negative outcomes of ADHD, including the rate of conduct disorder and adult antisocial personality disorder. Drug therapy is effective for all age groups, even preschoolers, and for late-onset ADHD in adults. Stimulants, such as methylphenidate and amphetamine, are the most effective therapy and have a good safety profile; although recent concerns of sudden unexplained death, psychiatric adverse effects, and growth effects have prompted the introduction of other therapies. Atomoxetine, a nonstimulant, has no abuse potential, causes less insomnia than stimulants, and poses minimal risk of growth effects. Other drug options include clonidine and guanfacine, but both can cause bradycardia and sedation. Polyunsaturated fatty acids (fish oil), acetyl-l-carnitine, and iron supplements (for youth with low ferritin levels) show promise in improving ADHD symptoms. As long-term studies show that at least 50% of youth are nonadherent with their drug therapy as prescribed over a 1-year period, longacting formulations (administered once/day) may improve adherence. Comorbid conditions are common in patients with ADHD, but this patient population can be treated effectively with individualized treatment regimens of stimulants, atomoxetine, or bupropion, along with close monitoring.

Attention-deficit-hyperactivity disorder: an update.

Context:Attention-deficit/hyperactivitydisorder(ADHD) is a common heritable childhood behavioral disorder. Identifying risk factors for ADHD may lead to improved intervention and prevention. The dopamine transporter gene (DAT1) is associated with ADHD in several studies, with an average 1.2 odds ratio and evidence of heterogeneity across data sets. Objective: To investigate sources of heterogeneity by refining the DAT1 association using additional markers and investigating gene-environment interaction betweenDAT1andmaternaluseofalcoholandtobaccoduring pregnancy. Design: Prospective study. Setting and Patients:Children with ADHD from child behavior clinics in the southeast of England and in the Taipei area of Taiwan.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209187/yoa40418.pdf

A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.

Jon Mill

Papers

A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.