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

  • Author(s): Gusev, Alexander;
  • Mancuso, Nicholas;
  • Won, Hyejung;
  • Kousi, Maria;
  • Finucane, Hilary K;
  • Reshef, Yakir;
  • Song, Lingyun;
  • Safi, Alexias;
  • Schizophrenia Working Group of the Psychiatric Genomics Consortium;
  • McCarroll, Steven;
  • Neale, Benjamin M;
  • Ophoff, Roel A;
  • O'Donovan, Michael C;
  • Crawford, Gregory E;
  • Geschwind, Daniel H;
  • Katsanis, Nicholas;
  • Sullivan, Patrick F;
  • Pasaniuc, Bogdan;
  • Price, Alkes L
  • et al.
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.

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