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

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, Christine, Renner, Tobias J., Walitza, Susanne, Warnke, Andreas, Palmason, Haukur, Buitelaar, Jan, Rommelse, Nanda, Vasquez, 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. (2011) 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: 195-204. doi:10.1176/appi.ajp.2011.11060822

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Author 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, Christine
Renner, Tobias J.
Walitza, Susanne
Warnke, Andreas
Palmason, Haukur
Buitelaar, Jan
Rommelse, Nanda
Vasquez, 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
Faraone, Stephen V.
Title Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3
Journal name American Journal of Psychiatry   Check publisher's open access policy
ISSN 1535-7228
0002-953X
Publication date 2011-12-15
Sub-type Article (original research)
DOI 10.1176/appi.ajp.2011.11060822
Volume 169
Issue 2
Start page 195
End page 204
Total pages 10
Place of publication Arlington, VA, United States
Publisher American Psychiatric Publishing
Collection year 2012
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes AJP in Advance - December 15, 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
 
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Created: Thu, 02 Feb 2012, 16:11:33 EST by Debra McMurtrie on behalf of Queensland Brain Institute