Identifying drug targets for schizophrenia through gene prioritization

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). To validate our findings, we compared them with previous prioritization efforts, known neurodevelopmental genes, and results from the PsyOPS tool.

We prioritized 62 schizophrenia genes, 41 of which were also highlighted by our validation methods. In addition to DRD2, the principal target of antipsychotics, we prioritized 9 genes that are targeted by approved or investigational drugs. These included drugs targeting glutamatergic receptors (GRIN2A and GRM3), calcium channels (CACNA1C and CACNB2), and GABA_B receptor (GABBR2). These also included genes in loci that are shared with an addiction GWAS (e.g. PDE4B and VRK2).

We curated a high-quality list of 62 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.