Exploring the Phenotypic Consequences of Tissue Specific Gene Expression Variation Inferred from GWAS Summary Statistics

Authors

Alvaro N. Barbeira, University of Chicago
Scott P. Dickinson, University of Chicago
Rodrigo Bonazzola, University of Chicago
Jiamao Zheng, University of Chicago
Heather E. Wheeler, Loyola University ChicagoFollow
Jason M. Torres, University of Chicago
Eric S. Torstenson, Vanderbilt University Medical Center
Kaanan P. Shah, University of Chicago
Tzintzuni Garcia, University of Chicago
Todd L. Edwards, Vanderbilt University Medical Center
Eli A. Stahl, Icahn School of Medicine at Mount Sinai
Laura M. Huckins, Icahn School of Medicine at Mount Sinai
GTEx Consortium
Dan L. Nicolae, University of Chicago
Nancy J. Cox, Vanderbilt University Medical Center
Hae Kyung Im, University of Chicago

Document Type

Article

Publication Date

5-8-2018

Publication Title

Nature Communications

Volume

9

Pages

1-20

Abstract

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

Comments

Author Posting. © The Authors 2018. This article is posted here by permission of Nature Research for personal use, not for redistribution. The article was published in Nature Communications, 2018, https://doi.org/10.1038/s41467-018-03621-1

Recommended Citation

Barbeira, Alvaro N.; Dickinson, Scott P.; Bonazzola, Rodrigo; Zheng, Jiamao; Wheeler, Heather E.; Torres, Jason M.; Torstenson, Eric S.; Shah, Kaanan P.; Garcia, Tzintzuni; Edwards, Todd L.; Stahl, Eli A.; Huckins, Laura M.; GTEx Consortium; Nicolae, Dan L.; Cox, Nancy J.; and Im, Hae Kyung. Exploring the Phenotypic Consequences of Tissue Specific Gene Expression Variation Inferred from GWAS Summary Statistics. Nature Communications, 9, : 1-20, 2018. Retrieved from Loyola eCommons, Biology: Faculty Publications and Other Works, http://dx.doi.org/10.1038/s41467-018-03621-1

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Copyright Statement

© The Authors 2018