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.

Links

Publisher Full Text

Authors

Williams NM, Franke B, Mick E, Anney RJ, Freitag CM, Gill M, Thapar A, O'Donovan MC, Owen MJ, Holmans P, Kent L, Middleton F, Zhang-James Y, Liu L, Meyer J, Nguyen TT, Romanos J, Romanos M, Seitz C, Renner TJ, Walitza S, Warnke A, Palmason H, Buitelaar J, Rommelse N, Vasquez AA, Hawi Z, Langley K, Sergeant J, Steinhausen HC, Roeyers H, Biederman J, Zaharieva I, Hakonarson H, Elia J, Lionel AC, Crosbie J, Marshall CR, Schachar R, Scherer SW, Todorov A, Smalley SL, Loo S, Nelson S, Shtir C, Asherson P, Reif A, Lesch KP, Faraone SV

Institution

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, and School of Medicine, Cardiff University, Cardiff, UK. williamsnm@cf.ac.uk

Source

The American journal of psychiatry 169:2 2012 Feb pg 195-204

MeSH

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

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22420048