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Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Williams, Nigel Melville, Franke, Barbara, Mick, Eric, Anney, Richard, Freitag, Christine M., Gill, Michael, Thapar, Anita, O'Donovan, Michael Conlon, Owen, Michael John, Holmans, Peter Alan, 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, Roeyers, Herbert, Biederman, Joseph, Zaharieva, Irina, Hakonarson, Hakon, Elia, Josephine, Lionel, Anath C., Crosbie, Jennifer, Marshall, Christian R., Schachar, Russell, Scherer, Stephen W., Todorov, Alexandre, Smalley, Susan L., Loo, Sandra, Nelson, Stanley, Shtir, Corina, Asherson, Philip, Reif, Andreas, Lesch, Klaus-Peter and Faraone, Stephen V. 2012. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. American Journal of Psychiatry 169 (2) , pp. 195-204. 10.1176/appi.ajp.2011.11060822

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Systems Immunity Research Institute (SIURI)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: American Psychiatric Publishing
ISSN: 0002-953X
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Last Modified: 08 May 2019 22:02
URI: http://orca.cf.ac.uk/id/eprint/30259

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