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Nat Genet DOI:10.1038/s41588-018-0092-1

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

Publication TypeJournal Article
Year of Publication2018
AuthorsGusev, A, Mancuso, N, Won, H, Kousi, M, Finucane, HK, Reshef, Y, Song, L, Safi, A, McCarroll, S, Neale, BM, Ophoff, RA, O'Donovan, MC, Crawford, GE, Geschwind, DH, Katsanis, N, Sullivan, PF, Pasaniuc, B, Price, AL
Corporate AuthorsSchizophrenia Working Group of the Psychiatric Genomics Consortium
JournalNat Genet
Volume50
Issue4
Pages538-548
Date Published2018 04
ISSN1546-1718
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.

DOI10.1038/s41588-018-0092-1
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29632383?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID29632383
PubMed Central IDPMC5942893
Grant ListP50 MH094268 / MH / NIMH NIH HHS / United States
R01 MH094714 / MH / NIMH NIH HHS / United States
F32 GM106584 / GM / NIGMS NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
R21 MH103877 / MH / NIMH NIH HHS / United States
U01 MH103365 / MH / NIMH NIH HHS / United States
R01 MH075916 / MH / NIMH NIH HHS / United States
R01 MH110927 / MH / NIMH NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U01 MH103392 / MH / NIMH NIH HHS / United States
U01 MH103346 / MH / NIMH NIH HHS / United States
R01 MH105472 / MH / NIMH NIH HHS / United States
U01 MH103340 / MH / NIMH NIH HHS / United States
P50 MH084053 / MH / NIMH NIH HHS / United States
U01 MH103339 / MH / NIMH NIH HHS / United States
R01 MH097276 / MH / NIMH NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
R01 MH093725 / MH / NIMH NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 GM105857 / GM / NIGMS NIH HHS / United States
U01 HG009379 / HG / NHGRI NIH HHS / United States
K99 MH113823 / MH / NIMH NIH HHS / United States
R01 HG009120 / HG / NHGRI NIH HHS / United States
R21 MH102791 / MH / NIMH NIH HHS / United States
R01 MH107649 / MH / NIMH NIH HHS / United States
R01 MH105898 / MH / NIMH NIH HHS / United States
R21 MH105881 / MH / NIMH NIH HHS / United States
HHSN271201300031C / MH / NIMH NIH HHS / United States
S10 OD018164 / OD / NIH HHS / United States
P50 MH066392 / MH / NIMH NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
R01 MH109978 / MH / NIMH NIH HHS / United States
R01 MH080405 / MH / NIMH NIH HHS / United States
U01 MH109528 / MH / NIMH NIH HHS / United States
R01 MH085542 / MH / NIMH NIH HHS / United States
P50 MH106934 / MH / NIMH NIH HHS / United States