Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3

Abstract

Objective:Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.Method:The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium.Results:The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.Conclusions:These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Rethinking the Concept of Psychosis and the Link Between Autism and Schizophrenia

“…Differences in the severity and type of information-processing deficits and neurocognitive impairments, together with the overall degree of neurobiological involvement, may contribute to the polymorphous and heterogeneous character of schizophrenia. Consistent with this hypothesis is that fact that increasing evidence suggests that schizophrenia shares common genes with autism and attentiondeficit/hyperactivity disorder (26)(27)(28)(29)(30)(31)(32)(33)(34). Furthermore, autism, attention-deficit/hyperactivity disorder, and schizophrenia may share neurocognitive impairments (35)(36)(37)(38)(39)(40)(41)(42)(43) and certain symptoms (44)(45)(46).…”

Academic textbooks on ADHD genetics: balanced or biased?

“…For instance, a duplication on the 15th chromosome at location 15q13.3 has a frequency of 1.25% in the research group of those diagnosed with ADHD. Although this is about two times higher than in the general population (0.6%) (Williams et al, 2012), it does not contribute much to the heritability of ADHD in general and many with the duplication do not display ADHD behaviours. The point that Barlow & Durand do not make relating to CNVs is that “the ESs of this and previous studies are quite small” (Martin, O’Donovan, Thapar, Langley, & Williams, 2015, p. 3).…”

CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree

“…4 Furthermore, the small CHRNA7 duplication was found as a risk factor for attention deficit hyperactivity disorder. 8 Here, we report triplication of CHRNA7, segregating in four affected family members in three generations (Figure 1). We present a detailed clinical and behavioral characterization of the affected individuals.…”