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Author Notes:

Correspondence should be addressed to G.G. (greg.gibson@biology.gatech.edu).

U.M.M. and G.G. conceived the theoretical framework for the TRSs.

L.A.D., J.S.H. and S.K. participated in the conception and design of the RISK study.

K.M., J.P., T.D.W., A.G., J.D.N., W.V.C., J.R.R., D.R.M., R.K., M.B.H., S.S.B., M.C.S., R.N.B., J.F.M., M.C.D., B.J.A., M.-O. K. and J.C. recruited subjects, collected the data, and worked on its curation and analysis.

U.M.M. performed the TRS analyses.

U.M.M. and G.G. interpreted the results and drafted the manuscript, while L.A.D., J.S.H. and S.K. assisted with results interpretation and writing.

We are grateful to B. Zeng, D. Arafat, H. Somineni, S. Venkateswaran, and colleagues from the Gibson and Kugathasan laboratories for their support and helpful comments.

We also would like to thank I. Mendizabal, J. Lachance and K. Jordan for comments on the manuscript.

The authors declare no competing financial interests.

Subject:

Research Funding:

This research was supported by Project 3 (G.G., PI) of the NIH program project “Statistical and Quantitative Genetics” grant P01-GM0996568 (B. Weir, University of Washington, Director) as well as research grants from the Crohn's and Colitis Foundation of America (CCFA), New York, to the individual study institutions participating in the RISK study.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • INFLAMMATORY-BOWEL-DISEASE
  • QUANTITATIVE TRAIT LOCI
  • GENOME-WIDE ASSOCIATION
  • GENE-EXPRESSION
  • SUSCEPTIBILITY LOCI
  • COLOCALIZATION
  • INTESTINE
  • INFECTION
  • VARIANTS
  • CHILDREN

Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease

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Journal Title:

Nature Genetics

Volume:

Volume 49, Number 10

Publisher:

, Pages 1517-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology1,2. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest2, we hypothesized that summation of risk-alleleassociated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease3,4. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment.

Copyright information:

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

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