TY - JOUR
T1 - Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder
T2 - The Role of Rare Variants and Duplications at 15q13.3
AU - Williams, Nigel M.
AU - Franke, Barbara
AU - Mick, Eric
AU - Anney, Richard J. L.
AU - Freitag, Christine M.
AU - Gill, Michael
AU - Thapar, Anita
AU - O'Donovan, Michael C.
AU - Owen, Michael J.
AU - Holmans, Peter
AU - Kent, Lindsey
AU - Middleton, Frank
AU - Zhang-James, Yanli
AU - Liu, Lu
AU - Meyer, Jobst
AU - Trang Nguyen, Thuy
AU - Romanos, Jasmin
AU - Romanos, Marcel
AU - Seitz, Christiane
AU - Renner, Tobias J.
AU - Walitza, Susanne
AU - Warnke, Andreas
AU - Palmason, Haukur
AU - Buitelaar, Jan
AU - Rommelse, Nanda
AU - Vasquez, Alejandro Arias
AU - Hawi, Ziarih
AU - Langley, Kate
AU - Sergeant, Joseph
AU - Steinhausen, Hans-Christoph
AU - Roeyers, Herbert
AU - Biederman, Joseph
AU - Zaharieva, Irina
AU - Hakonarson, Hakon
AU - Elia, Josephine
AU - Lionel, Anath C.
AU - Crosbie, Jennifer
AU - Marshall, Christian R.
AU - Schachar, Russell
AU - Scherer, Stephen W.
AU - Todorov, Alexandre
AU - Smalley, Susan L.
AU - Loo, Sandra
AU - Nelson, Stanley
AU - Shtir, Corina
AU - Asherson, Philip
AU - Reif, Andreas
AU - Lesch, Klaus-Peter
AU - Faraone, Stephen V.
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
U2 - 10.1176/appi.ajp.2011.11060822
DO - 10.1176/appi.ajp.2011.11060822
M3 - Article
SN - 0002-953X
VL - 169
SP - 195
EP - 204
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 2
ER -