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

Alexander Gusev, Nicholas Mancuso, Hyejung Won, Maria Kousi, Hilary K. Finucane, Yakir Reshef, Lingyun Song, Alexias Safi, Steven McCarroll, Benjamin M. Neale, Roel A. Ophoff, Michael C. O'Donovan, Gregory E. Crawford, Daniel H. Geschwind, Elias Nicholas Katsanis, Patrick F. Sullivan, Bogdan Pasaniuc, Alkes L. Price

Research output: Contribution to journalArticle

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)538-548
Number of pages11
JournalNature Genetics
Volume50
Issue number4
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Genetics

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    Gusev, A., Mancuso, N., Won, H., Kousi, M., Finucane, H. K., Reshef, Y., Song, L., Safi, A., McCarroll, S., Neale, B. M., Ophoff, R. A., O'Donovan, M. C., Crawford, G. E., Geschwind, D. H., Katsanis, E. N., Sullivan, P. F., Pasaniuc, B., & Price, A. L. (2018). Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nature Genetics, 50(4), 538-548. https://doi.org/10.1038/s41588-018-0092-1