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

Nat Genet. 2018 Apr;50(4):538-548. doi: 10.1038/s41588-018-0092-1. Epub 2018 Apr 9.

Abstract

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. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus 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 the brain captured most 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 toward a mechanistic understanding of GWAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Chromatin / genetics*
  • Gene Dosage
  • Gene Expression Profiling / methods
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Multifactorial Inheritance
  • Protein Phosphatase 2 / genetics
  • Quantitative Trait Loci
  • Schizophrenia / etiology*
  • Schizophrenia / genetics*
  • Zebrafish / genetics
  • Zebrafish / growth & development
  • Zebrafish Proteins / genetics

Substances

  • Chromatin
  • Microtubule-Associated Proteins
  • PPP2R3C protein, human
  • Zebrafish Proteins
  • kinesin light-chain proteins
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 3
  • Protein Phosphatase 2

Grant support