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Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
AU - Gusev, Alexander
AU - Mancuso, Nicholas
AU - Won, Hyejung
AU - Kousi, Maria
AU - Finucane, Hilary K
AU - Reshef, Yakir
AU - Song, Lingyun
AU - Safi, Alexias
AU - McCarroll, Steven
AU - Neale, Benjamin M
AU - Ophoff, Roel A
AU - O'Donovan, Michael C
AU - Crawford, Gregory E
AU - Geschwind, Daniel H
AU - Katsanis, Nicholas
AU - Sullivan, Patrick F
AU - Pasaniuc, Bogdan
AU - Price, Alkes L
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Knight, Jo
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-018-0092-1
DO - 10.1038/s41588-018-0092-1
M3 - Journal article
C2 - 29632383
VL - 50
SP - 538
EP - 548
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -