Poster 8
Presenter: Amy Hart
Thursday, 4:00 – 6:00pm
Amy B. Hart1, Eric R. Gamazon2, Harriet de Wit3, Nancy J. Cox1,2, Abraham A. Palmer1,3 1Department of Human Genetics, University of Chicago, 2Department of Medicine, University of Chicago, 3Department of Psychiatry and Behavioral Neuroscience, University of Chicago
Genome-wide association studies (GWAS) provide an unbiased approach to investigating the contribution of genetic variation throughout the genome to a phenotype of interest. However, an underlying assumption of GWAS is that all variants (single nucleotide polymorphisms, or SNPs) are equally likely to have an effect on a phenotype, despite that fact that most SNPs do not have functional consequences. We previously performed a GWAS for the acute response to d-amphetamine in 381 healthy human volunteers. In an effort to interrogate the numerous non-significant associations we identified, we sought to identify enrichment of functional classes of SNPs among our top GWAS associations with response to d-amphetamine. We found that SNPs with modestly low P-values (P<0.01) for response to d-amphetamine were significantly more likely than random to have similarly low P-values for schizophrenia and Attention Deficit Hyperactivity Disorder (ADHD). Furthermore, the source of this enrichment was due to an excess of alleles that increased sensitivity to the subjectively positive effects of d-amphetamine and that also increased risk for these diseases. We found no enrichment for negative control phenotypes such as height and inflammatory bowel disease. These results suggest that alleles identified using an acute challenge with a dopaminergic drug can be used to identify alleles that confer risk for psychiatric diseases that are associated with dopaminergic abnormalities. Moreover, they demonstrate the utility of the enrichment approach as an alternative to stringent standards for genome-wide significance.