Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS significant genes, of which 35 did not overlap a known GWAS locus. 42/157 genes were associated to specific chromatin features measured in independent samples, highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, MAPK3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from brain captured the majority of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving towards a mechanistic understanding of GWAS.