Drug enrichment and discovery from schizophrenia genome-wide association results: an analysis and visualisation approach

H A Gaspar,H A Gaspar,G Breen,G Breen,G Breen

doi:10.1038/s41598-017-12325-3

Abstract

Using successful genome-wide association results in psychiatry for drug repurposing is an ongoing challenge. Databases collecting drug targets and gene annotations are growing and can be harnessed to shed a new light on psychiatric disorders. We used genome-wide association study (GWAS) summary statistics from the Psychiatric Genetics Consortium (PGC) Schizophrenia working group to build a drug repositioning model for schizophrenia. As sample size increases, schizophrenia GWAS results show increasing enrichment for known antipsychotic drugs, selective calcium channel blockers, and antiepileptics. Each of these therapeutical classes targets different gene subnetworks. We identify 123 Bonferroni-significant druggable genes outside the MHC, and 128 FDR-significant biological pathways related to neurons, synapses, genic intolerance, membrane transport, epilepsy, and mental disorders. These results suggest that, in schizophrenia, current well-powered GWAS results can reliably detect known schizophrenia drugs and thus may hold considerable potential for the identification of new therapeutic leads. Moreover, antiepileptics and calcium channel blockers may provide repurposing opportunities. This study also reveals significant pathways in schizophrenia that were not identified previously, and provides a workflow for pathway analysis and drug repurposing using GWAS results.

Highlights

Genome-wide association studies (GWAS) have been performed on numerous human disorders and traits[1], uncovering thousands of associations between disorders or quantitative phenotypes and common genetic variants, usually single nucleotide polymorphisms (SNPs), that ‘tag’ or identify specific genetic loci
The analysis revealed that enriched drug classes targeted different subnetworks with association with schizophrenia
We find that the targets of antipsychotics, the primary drug class used to treat schizophrenia, are enriched for association in current schizophrenia genome-wide association study (GWAS) results

Summary

Introduction

Genome-wide association studies (GWAS) have been performed on numerous human disorders and traits[1], uncovering thousands of associations between disorders or quantitative phenotypes and common genetic variants, usually single nucleotide polymorphisms (SNPs), that ‘tag’ or identify specific genetic loci. Recent studies have shown how pathway analysis on GWAS data could help discover new drugs for schizophrenia[10,11,12]. These studies, as well as studies focused on single genes or targets, have generally lacked a step to show if a GWAS has sufficient power to reliably identify known drugs; this is a critical step that would lend confidence to the discovery of novel drug associations in GWAS data. We analysed the complete SCZ-PGC2 GWAS for the associations of gene families, gene ontology (GO) pathways, canonical pathways, disease pathways, drugs and drug classes with schizophrenia. We propose a new workflow to visualise and cluster significant biological pathways by accounting for pathway similarities as well as pathway significance, based on a kernel variant of the Generative Topographic Mapping approach[15,16]

Methods

Results

Conclusion