Identifying drug targets for schizophrenia through gene prioritization

Abstract

Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts have mostly been restricted to locus-based methods that ignore information from the rest of the genome. To more accurately characterize genes involved in schizophrenia etiology, we applied a combination of highly-predictive tools to a published GWAS of 67,390 schizophrenia cases and 94,015 controls. We combined both locus-based methods (fine-mapped coding variants, distance to GWAS signals) and genome-wide methods (PoPS, MAGMA, ultra-rare coding variant burden tests). We extracted genes that 1) are targeted by existing drugs that could potentially be repurposed for schizophrenia, 2) are predicted to be druggable, or 3) may be testable in rodent models. We prioritized 101 schizophrenia genes, including 15 that are targeted by approved or investigational drugs (e.g., DRD2, GRIN2A, CACNA1C, GABBR2). Of these, 7 have never been tested in clinical trials for schizophrenia or other psychiatric disorders (e.g., AKT3). Seven genes are not targeted by any existing small molecule drugs, but are predicted to be druggable (e.g., GRM1). We prioritized two potentially druggable genes in loci that are shared with an addiction GWAS (PDE4B and VRK2). We curated a high-quality list of 101 genes that likely play a role in the development of schizophrenia. Developing or repurposing drugs that target these genes may lead to a new generation of schizophrenia therapies. Rodent models of addiction more closely resemble the human disorder than rodent models of schizophrenia. As such, genes prioritized for both disorders could be explored in rodent addiction models, potentially facilitating drug development.