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Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

2010; Elsevier BV; Volume: 49; Issue: 9 Linguagem: Inglês

10.1016/j.jaac.2010.06.008

1527-5418

Benjamin M. Neale, Sarah E. Medland, Stephan Ripke, Philip Asherson, Barbara Franke, Klaus‐Peter Lesch, Stephen V. Faraone, Thuy Trang Nguyen, H. Schäfer, Peter Holmans, Mark J. Daly, Hans‐Christoph Steinhausen, Christine M. Freitag, Andreas Reif, Tobias Renner, Marcel Romanos, Jasmin Romanos, Susanne Walitza, Andreas Warnke, Jobst Meyer, Haukur Pálmason, Jan K. Buitelaar, Alejandro Arias Väsquez, Nanda Lambregts-Rommelse, Michael Gill, Richard Anney, Kate Langely, Michael O’Donovan, Nigel Williams, Michael J. Owen, Anita Thapar, Lindsey Kent, Joseph A. Sergeant, Herbert Roeyers, Eric Mick, Joseph Biederman, Alysa E. Doyle, Susan L. Smalley, Sandra K. Loo, Hákon Hákonarson, Josephine Elia, Alexandre A. Todorov, Ana Miranda, Fernando Mulas, Richard P. Ebstein, Aribert Rothenberger, Tobias Banaschewski, Robert D. Oades, Edmund Sonuga‐Barke, James J. McGough, Laura Nisenbaum, Frank A. Middleton, Xiaolan Hu, Stan F. Nelson,

Bipolar Disorder and Treatment

Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability. Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.