When GWAS meets the Connectivity Map: drug repositioning for seven psychiatric disorders

Abstract

AbstractOur knowledge of disease genetics has advanced rapidly during the past decade, with the advent of high-throughput genotyping technologies such as genome-wide association studies (GWAS). However, few methodologies were developed and systemic studies performed to identify novel drug candidates utilizing GWAS data. In this study we focus on drug repositioning, which is a cost-effective approach to shorten the developmental process of new therapies. We proposed a novel framework of drug repositioning by comparing GWAS-imputed transcriptome with drug expression profiles from the Connectivity Map. The approach was applied to 7 psychiatric disorders. We discovered a number of novel repositioning candidates, many of which are supported by preclinical or clinical evidence. We found that the predicted drugs are significantly enriched for known psychiatric medications, or therapies considered in clinical trials. For example, drugs repurposed for schizophrenia are strongly enriched for antipsychotics (p = 4.69E-06), while those repurposed for bipolar disorder are enriched for antipsychotics (p = 2.26E-07) and antidepressants (p = 1.17E-05). These findings provide support to the usefulness of GWAS signals in guiding drug discoveries and the validity of our approach in drug repositioning. We also present manually curated lists of top repositioning candidates for each disorder, which we believe will serve as a useful resource for researchers.