High-throughput allele-specific expression across 250 environmental conditions
- Gregory A Moyerbrailean1,
- Allison L Richards1,
- Daniel Kurtz1,
- Cynthia A Kalita1,
- Gordon O Davis1,
- Chris T Harvey1,
- Adnan Alazizi1,
- Donovan Watza1,
- Yoram Sorokin1,
- Nancy Hauff1,
- Xiang Zhou2,
- Xiaoquan Wen2,
- Roger Pique-Regi1 and
- Francesca Luca1,3
- ↵* Corresponding author; email: fluca{at}wayne.edu
Abstract
Gene-by-environment interactions (GxE) determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on sub-cellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE in gene expression patterns by exploiting naturally-occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in 5 cell types. We discovered 1,455 genes with allele-specific expression (ASE) (FDR<10%) and 215 genes with GxE. We demonstrated a major role for GxE in complex traits. Genes with a transcriptional response to environmental perturbations showed a 7-fold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity, and LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genome-wide association studies.
- Received May 12, 2016.
- Accepted October 13, 2016.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
