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, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Steven McCarroll, Benjamin M Neale, Roel A Ophoff, Michael C O'Donovan, Gregory E Crawford, Daniel H Geschwind, Nicholas Katsanis, Patrick F Sullivan, Bogdan Pasaniuc, Alkes L Price, Alexander Gusev, Nicholas Mancuso, Hyejung Won, Maria Kousi, Hilary K Finucane, Yakir Reshef, Lingyun Song, Alexias Safi, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Steven McCarroll, Benjamin M Neale, Roel A Ophoff, Michael C O'Donovan, Gregory E Crawford, Daniel H Geschwind, Nicholas Katsanis, Patrick F Sullivan, Bogdan Pasaniuc, Alkes L Price
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.
Conflict of interest statement
The authors declare no competing financial interests.
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References
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