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

Academic Article

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.
  • Authors

    Keywords

  • Animals, Brain, Chromatin, Gene Dosage, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Microtubule-Associated Proteins, Mitogen-Activated Protein Kinase 3, Multifactorial Inheritance, Protein Phosphatase 2, Quantitative Trait Loci, Schizophrenia, Zebrafish, Zebrafish Proteins
  • Digital Object Identifier (doi)

    Pubmed Id

  • 8854532
  • Author List

  • Gusev A; Mancuso N; Won H; Kousi M; Finucane HK; Reshef Y; Song L; Safi A; Schizophrenia Working Group of the Psychiatric Genomics Consortium; McCarroll S
  • Start Page

  • 538
  • End Page

  • 548
  • Volume

  • 50
  • Issue

  • 4