We show that the genetic susceptibility to the euphoric effects of d-amphetamine also influences the genetic predisposition to schizophrenia and attention deficit hyperactivity disorder (ADHD). These results reinforce the idea that dopamine plays a role in schizophrenia and ADHD; this so-called dopamine hypothesis has been debated for several decades. Specifically, we found that the alleles associated with increased euphoric response to d-amphetamine were associated with decreased risk for schizophrenia and ADHD. These results illustrate how an acute challenge with a pharmacological agent can reveal a genetic predisposition that will manifest itself as psychiatric illness over the lifetime of an individual. Finally, our study offers a relatively novel paradigm for the analysis of endophenotypes for which large sample sizes are not typically available.

Abstract

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.