Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder
Neale, Benjamin M., Medland, Sarah E., Ripke, Stephan, Asherson, Philip, Franke, Barbara, Lesch, Klaus Peter, Faraone, Stephen V., Nguyen, Thuy Trang, Schäfer, Helmut, Holmans, Peter, Daly, Mark, Steinhausen, Hans-Christoph, Freitag, Christine, Reif, Andreas, Renner, Tobias J., Romanos, Marcel, Romanos, Jasmin, Walitza, Susanne, Warnke, Andreas, Meyer, Jobst, Pálmason, Haukur, Buitelaar, Jan K, Vasquez, Alejandro Arias, Lambregts-Rommelse, Nanda, Gill, Michael, Anney, Richard J.L., Langely, Kate, O’Donovan, Michael, Williams, Nigel, Owen, Michael, Thapar, Anita, Kent, Lindsey, Sergeant, Joseph A, Roeyers, Herbert, Mick, Eric, Biederman, Joseph, Doyle, Alysa, Smalley, Susan L., Loo, Sandra K., Hakonarson, Hakon, Elia, Josephine, Todorov, Alexandre, Miranda, Ana, Mulas, Fernando, Ebstein, Richard, Rothenberger, Aribert, Banaschewski, Tobias, Oades, Robert D., Sonuga-Barke, Edmund J.S., McGough, James J., Nisenbaum, Laura, Middleton, Frank, Hu, Xiaolan, Nelson, Stanley F.
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 scans (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 the 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 SNPs, 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 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.