Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder

Amy B. Hart, Eric R. Gamazon, Barbara E. Engelhardt, Pamela Sklar, Anna K. Kähler, Christina M. Hultman, Patrick F. Sullivan, Benjamin M. Neale, Stephen V. Faraone, Harriet de Wit, Nancy J. Cox, Abraham A. Palmer, Richard Anney, Philip Asherson, Tobias Banaschewski, Mònica Bayés, Joseph Biederman, Jan K. Buitelaar, Miquel Casas, Bru Cormand, Jennifer Crosbie, Alysa E. Doyle, Josephine Elia, Stephen V. Faraone, Barbara Franke, Lindsey Kent, Jonna Kuntsi, Klaus-Peter Lesch, Sandra K. Loo, James J. McGough, Sarah E. Medland, Benjamin Neale, Stan F. Nelson, Robert D. Oades, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Aribert Rothenberger, Russell Schachar, Susan L. Smalley, Edmund Sonuga-Barke, Hans-Christoph Steinhausen, Anita Thapar, Nigel Williams

Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.