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

Nigel M. Williams, Barbara Franke, Eric Mick, Richard J. L. Anney, Christine M. Freitag, Michael Gill, Anita Thapar, Michael C. O'Donovan, Michael J. Owen, Peter A. Holmans, Lindsey Kent, Frank Middleton, Yanli Zhang-James, Lu Liu, Jobst Meyer, Thuy Trang Nguyen, Jasmin Romanos, Marcel Romanos, Christiane Seitz, Tobias J RennerSusanne Walitza, Andreas Warnke, Haukur Palmason, Jan Buitelaar, Nanda Rommelse, Alejandro Arias Vasquez, Ziarih Hawi, Kate Langley, Joseph A. Sergeant, Hans-Christoph Steinhausen, Herbert Roeyers, Joseph Biederman, Irina T. Zaharieva, Hakon Hakonarson, Josephine Elia, Anath C. Lionel, Jennifer Crosbie, Christian R. Marshall, Russell Schachar, Stephen W. Scherer, Alexandre A. Todorov, Susan L. Smalley, Sandra K. Loo, Stanley Nelson, Corina Shtir, Philip Asherson, Andreas Reif, Klaus-Peter Lesch, Stephen V. Faraone*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.The authors performed a genome-wide analysis of large, 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.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.
Original languageEnglish
Pages (from-to)195-204
JournalAmerican Journal of Psychiatry
Issue number2
Publication statusPublished - Feb 2012


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