Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder.
Neale, Benjamin M. Ph.D. a,b; Medland, Sarah E. Ph.D. c,d; Ripke, Stephan M.D. a,b; Asherson, Philip M.R.C.Psych., Ph.D. e; Franke, Barbara Ph.D. f; Lesch, Klaus-Peter M.D. m; Faraone, Stephen V. Ph.D. g*; Nguyen, Thuy Trang Dipl. Math. oec. h; Schafer, Helmut Ph.D. h; Holmans, Peter Ph.D. i; Daly, Mark Ph.D. a,d; Steinhausen, Hans-Christoph M.D., Ph.D., D.M.Sc. j,k,l; Freitag, Christine M.D., M.A. n; Reif, Andreas M.D. m; Renner, Tobias J. M.D. m; Romanos, Marcel M.D. m; Romanos, Jasmin M.D. m; Walitza, Susanne M.D. j,m; Warnke, Andreas M.D., Ph.D. m; Meyer, Jobst Ph.D. o; Palmason, Haukur Ph.D. o; Buitelaar, Jan M.D. f; Vasquez, Alejandro Arias Ph.D. f; Lambregts-Rommelse, Nanda Ph.D. f; Gill, Michael Mb B.Ch. B.A.O., M.D., M.R.C.Psych., F.T.C.D. p; Anney, Richard J.L. Ph.D. p; Langely, Kate Ph.D. i; O'Donovan, Michael F.R.C.Psych., Ph.D. q; Williams, Nigel Ph.D. q; Owen, Michael Ph.D., F.R.C.Psych. i; Thapar, Anita M.D. i; Kent, Lindsey M.D., Ph.D. r; Sergeant, Joseph Ph.D. s; Roeyers, Herbert M.D., Ph.D. t; Mick, Eric Sc.D. s,t; Biederman, Joseph M.D. u,v; Doyle, Alysa Ph.D. r,s; Smalley, Susan Ph.D. w; Loo, Sandra Ph.D. w; Hakonarson, Hakon M.D., Ph.D. x,y; Elia, Josephine M.D. x; Todorov, Alexandre Ph.D. z; Miranda, Ana M.D. aa; Mulas, Fernando M.D., Ph.D. ab; Ebstein, Richard P. Ph.D. ac; Rothenberger, Aribert M.D., Ph.D. ad; Banaschewski, Tobias M.D., Ph.D. n; Oades, Robert D. Ph.D. ae; Sonuga-Barke, Edmund Ph.D. e,af,ag; McGough, James M.D. w; Nisenbaum, Laura Ph.D. ah; Middleton, Frank Ph.D. f; Hu, Xiaolan Ph.D. ai; Nelson, Stan M.D. aj; Psychiatric GWAS Consortium: ADHD Subgroup
Journal of the American Academy of Child & Adolescent Psychiatry.
49(9):884-897, September 2010.
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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.
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