Skip to main content

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

Publication ,  Journal Article
Gusev, A; Mancuso, N; Won, H; Kousi, M; Finucane, HK; Reshef, Y; Song, L; Safi, A; McCarroll, S; Neale, BM; Ophoff, RA; O'Donovan, MC ...
Published in: Nat Genet
April 2018

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2018

Volume

50

Issue

4

Start / End Page

538 / 548

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Schizophrenia
  • Quantitative Trait Loci
  • Protein Phosphatase 2
  • Multifactorial Inheritance
  • Mitogen-Activated Protein Kinase 3
  • Microtubule-Associated Proteins
  • Kinesins
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gusev, A., Mancuso, N., Won, H., Kousi, M., Finucane, H. K., Reshef, Y., … Price, A. L. (2018). Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet, 50(4), 538–548. https://doi.org/10.1038/s41588-018-0092-1
Gusev, Alexander, Nicholas Mancuso, Hyejung Won, Maria Kousi, Hilary K. Finucane, Yakir Reshef, Lingyun Song, et al. “Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.Nat Genet 50, no. 4 (April 2018): 538–48. https://doi.org/10.1038/s41588-018-0092-1.
Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018 Apr;50(4):538–48.
Gusev, Alexander, et al. “Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.Nat Genet, vol. 50, no. 4, Apr. 2018, pp. 538–48. Pubmed, doi:10.1038/s41588-018-0092-1.
Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, Song L, Safi A, Schizophrenia Working Group of the Psychiatric Genomics Consortium, McCarroll S, Neale BM, Ophoff RA, O’Donovan MC, Crawford GE, Geschwind DH, Katsanis N, Sullivan PF, Pasaniuc B, Price AL. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018 Apr;50(4):538–548.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

April 2018

Volume

50

Issue

4

Start / End Page

538 / 548

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Schizophrenia
  • Quantitative Trait Loci
  • Protein Phosphatase 2
  • Multifactorial Inheritance
  • Mitogen-Activated Protein Kinase 3
  • Microtubule-Associated Proteins
  • Kinesins
  • Humans