Title

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

Authors

Nigel M. Williams, Cardiff University
Barbara Franke, Cardiff University
Eric Mick, University of Massachusetts Medical SchoolFollow
Richard J. Anney, Cardiff University
Christine M. Freitag, Cardiff University
Michael Gill, Cardiff University
Anita Thapar, Cardiff University
Michael C. O'Donovan, Cardiff University
Michael J. Owen, Cardiff University
Peter Holmans, Cardiff University
Lindsey Kent, Cardiff University
Frank Middleton, Cardiff University
Yanli Zhang-James, Cardiff University
Lu Liu, Cardiff University
Jobst Meyer, Cardiff University
Thuy Trang Nguyen, Cardiff University
Jasmin Romanos, Cardiff University
Marcel romanos, Cardiff University
Christiane Seitz, Cardiff University
Tobias J. Renner, Cardiff University
Susanne Walitza, Eli Lilly
Andreas Warnke, Cardiff University
Haukur Palmason, Cardiff University
Jan Buitelaar, Bristol-Myers Squibb
Nanda Rommelse, Cardiff University
Alejandro Arias Vasquez, Cardiff University
Ziarih Hawi, Wellcome Trust and the Health Research Board Ireland
Kate Langley, Cardiff University
Joseph Sergeant, Cardiff University
Hans-Christoph Steinhausen, Cardiff University
Herbert Roeyers, Cardiff University
Joseph Biederman, Harvard Medical School
Irina Zaharieva, Cardiff University
Hakon Hakonarson, Cardiff University
Josephine Elia, Cardiff University
Anath C. Lionel, Cardiff University
Jennifer Crosbie, Cariff University
Christian R. Marshall, Cardiff University
Russell Schachar, Cardiff University
Stephen W. Scherer, Cardiff University
Alexandre Todorov, Cardiff University
Susan L. Smalley, University of California
Sandra K. Loo, University of California
Stanley Nelson, Cardiff University
Corina Shtir, University of Cambridge
Philip Asherson, Cardiff University
Andreas Reif, Cardiff University
Klaus-Peter Lesch, Cardiff University
Stephen V. Faraone, Harvard Medical School

UMMS Affiliation

Department of Quantitative Health Sciences

Date

2-2012

Document Type

Article

Medical Subject Headings

Adolescent; *Attention Deficit Disorder with Hyperactivity; Canada; Causality; Child; Child, Preschool; Female; *Gene Dosage; Genetic Predisposition to Disease; Genome-Wide Association Study; Great Britain; Humans; In Situ Hybridization, Fluorescence; Inheritance Patterns; Polymorphism, Single Nucleotide; Receptors, Nicotinic; Segmental Duplications, Genomic; United States

Disciplines

Genetics and Genomics | Psychiatry and Psychology

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 (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.

Rights and Permissions

Citation: Am J Psychiatry. 2012 Feb;169(2):195-204.

Related Resources

Link to Article in PubMed