title: High-throughput allele-specific expression across 250 environmental conditions.
abstract: Gene-by-environment (GxE) interactions 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 subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions 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 interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include 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.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Moyerbrailean
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kurtz
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Kalita
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Gordon O
authors.initials: GO
authors.lastname: Davis
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Chris T
authors.initials: CT
authors.lastname: Harvey
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Alazizi
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Donovan
authors.initials: D
authors.lastname: Watza
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Sorokin
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hauff
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoquan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.|Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Pique-Regi
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201, USA.|Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Luca
mesh_terms: D000483:Alleles; D002110:Caffeine / Q000494:pharmacology; D002460:Cell Line; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study / Q000379:methods*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects; D040641:Quantitative Trait Loci / Q000187:drug effects*; D012643:Selenium / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D014415:Tunicamycin; D002110:Caffeine; D012643:Selenium