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

Article English OPEN
Williams, Nigel M. ; Franke, Barbara ; Mick, Eric ; Anney, Richard J.L. ; Freitag, Christine M. ; Gill, Michael ; Thapar, Anita ; O'Donovan, Michael C. ; Owen, Michael J. ; Holmans, Peter ; Kent, Lindsey ; Middleton, Frank ; Zhang-James, Yanli ; Liu, Lu ; Meyer, Jobst ; Nguyen, Thuy Trang ; Romanos, Jasmin ; Romanos, Marcel ; Seitz, Christiane ; Renner, Tobias J. ; Walitza, Susanne ; Warnke, Andreas ; Palmason, Haukur ; Buitelaar, Jan ; Rommelse, Nanda ; Vasquez, Alejandro Arias ; Hawi, Ziarih ; Langley, Kate ; Sergeant, Joseph ; Steinhausen, Hans-Christoph ... view all 49 authors (2013)
  • Publisher: American Psychiatric Publishing
  • Journal: volume 169, issue 2, pages 195-204 (issn: 0002-953X, eissn: 1535-7228)
  • Related identifiers: doi: 10.1176/appi.ajp.2011.11060822, pmc: PMC3601405
  • Subject: RC0321 | CHROMOSOMAL DELETIONS | ASSOCIATION SCAN | DEFICIT/HYPERACTIVITY DISORDER | Neuroscience | QH426 | SCHIZOPHRENIA | New Research | ADHD | Genes & Society | MOLECULAR-GENETICS | CANDIDATE GENE | Social Sciences | MICRODUPLICATIONS | NICOTINIC RECEPTOR | AUTISM SPECTRUM DISORDER | Articles | R1
    mesheuropmc: mental disorders

OBJECTIVE:\ud 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.\ud METHOD:\ud 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.\ud RESULTS:\ud 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.\ud CONCLUSIONS:\ud 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.