PUBLICATION
Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
- Authors
- Gusev, A., Mancuso, N., Won, H., Kousi, M., Finucane, H.K., Reshef, Y., Song, L., Safi, A., Schizophrenia Working Group of the Psychiatric Genomics Consortium, McCarroll, S., Neale, B.M., Ophoff, R.A., O'Donovan, M.C., Crawford, G.E., Geschwind, D.H., Katsanis, N., Sullivan, P.F., Pasaniuc, B., Price, A.L.
- ID
- ZDB-PUB-180418-3
- Date
- 2018
- Source
- Nature Genetics 50: 538-548 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Genetic Predisposition to Disease
- Multifactorial Inheritance
- Chromatin/genetics*
- Quantitative Trait Loci
- Gene Expression Profiling/methods
- PubMed
- 29632383 Full text @ Nat. Genet.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping