Journal Article

Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Garcia, Tzintzuni, Torstenson, Eric S., Barbeira, Alvaro N., Im, Hae Kyung, Wheeler, Heather E., Nicolae, Dan L., Stahl, Eli A., Huckins, Laura M., Torres, Jason M., Zheng, Jiamao, Cox, Nancy J., Shah, Kaanan P., Bonazzola, Rodrigo, Edwards, Todd L., Dickinson, Scott P.

2018

Overview

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. Phenotypic variation and diseases are influenced by factors such as genetic variants and gene expression. Here, Barbeira et al. develop S-PrediXcan to compute PrediXcan results using summary data, and investigate the effects of gene expression variation on human phenotypes in 44 GTEx tissues and >100 phenotypes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/43 / 45 / 631/114/2401 / 631/208/205/2138 / Chromosome Mapping - methods / Computer Simulation / Etiology / Gene Expression / Gene mapping / Genes / Genetic diversity / Genetic variance / Genetic Variation / Genome-Wide Association Study - statistics & numerical data / Humanities and Social Sciences / Humans / Meta-Analysis as Topic / Models, Genetic / multidisciplinary / Organ Specificity / Phenotype / Phenotypic variations / Polymorphism, Single Nucleotide / Quantitative Trait Loci / Regulatory mechanisms (biology) / Robustness (mathematics) / Science / Science (multidisciplinary) / Statistical analysis / Statistical methods