Gene-level analysis reveals the genetic aetiology and therapeutic targets of schizophrenia

Abstract

Genome-wide association studies (GWASs) have reported multiple risk loci for schizophrenia (SCZ). However, the majority of the associations were from populations of European ancestry. Here we conducted a large-scale GWAS in Eastern Asian populations (29,519 cases and 44,392 controls) and identified ten Eastern Asian-specific risk loci, two of which have not been previously reported. A further cross-ancestry GWAS meta-analysis (96,806 cases and 492,818 controls) including populations from diverse ancestries identified 61 previously unreported risk loci. Systematic variant-level analysis, including fine mapping, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, proteome-wide association study and Mendelian randomization, nominated the potential causal genes. By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for SCZ, such as ACE, CNNM2, SNAP91, ABCB9 and GATAD2A. Finally, drug repurposing showed that ACE, CA14, MAPK3 and MAPT are potential therapeutic targets for SCZ. Our study not only showed the power of cross-ancestry GWAS in deciphering the genetic aetiology of SCZ, but also uncovered new genetic risk loci, potential causal variants and genes and therapeutic targets for SCZ.