PT  - JOURNAL ARTICLE
AU  - Alvaro N. Barbeira
AU  - Scott P. Dickinson
AU  - Jason M. Torres
AU  - Jiamao Zheng
AU  - Eric S. Torstenson
AU  - Heather E. Wheeler
AU  - Kaanan P. Shah
AU  - Rodrigo Bonazzola
AU  - Tzintzuni Garcia
AU  - Todd Edwards
AU  - GTEx Consortium
AU  - Dan L. Nicolae
AU  - Nancy J. Cox
AU  - Hae Kyung Im
TI  - Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
AID  - 10.1101/045260
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 045260
4099  - http://biorxiv.org/content/early/2017/10/03/045260.short
4100  - http://biorxiv.org/content/early/2017/10/03/045260.full
AB  - 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 were 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.