Interactions between genetic variation and cellular environment in skeletal muscle gene expression

• Published in: PloS one 2018-04, Vol.13 (4), p.e0195788
• Main Authors: Taylor, D Leland, Knowles, David A, Scott, Laura J, Ramirez, Andrea H, Casale, Francesco Paolo, Wolford, Brooke N, Guan, Li, Varshney, Arushi, Albanus, Ricardo D'Oliveira, Parker, Stephen C J, Narisu, Narisu, Chines, Peter S, Erdos, Michael R, Welch, Ryan P, Kinnunen, Leena, Saramies, Jouko, Sundvall, Jouko, Lakka, Timo A, Laakso, Markku, Tuomilehto, Jaakko, Koistinen, Heikki A, Stegle, Oliver, Boehnke, Michael, Birney, Ewan, Collins, Francis S
• Format: Article
• Language: English
• Subjects: Bioinformatics; Biology and Life Sciences; Blood pressure; Cellular Microenvironment; Cholesterol; Consortia; Deoxyribonucleic acid; Diabetes; DNA; Energy Metabolism; Environment; Environmental conditions; Environmental effects; Gene expression; Gene Expression Regulation; Gene sequencing; Gene-Environment Interaction; Genetic Association Studies; Genetic diversity; Genetic effects; Genetic Variation; Genetics; Genomes; Genotype; Genotype-environment interactions; Genotypes; Health aspects; Health care; Heterozygotes; Hospitals; Humans; Laboratories; Medicine and Health Sciences; Methods; Molecular biology; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscles; Phenotype; Phenotyping; Physiology; Polymorphism, Single Nucleotide; Preventive medicine; Proteins; Public health; Quantitative Trait Loci; Replication; Research and Analysis Methods; Ribonucleic acid; RNA; Single-nucleotide polymorphism; Skeletal muscle; Transcription factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195788

From whole organisms to individual cells, responses to environmental conditions are influenced by genetic makeup, where the effect of genetic variation on a trait depends on the environmental context. RNA-sequencing quantifies gene expression as a molecular trait, and is capable of capturing both genetic and environmental effects. In this study, we explore opportunities of using allele-specific expression (ASE) to discover cis-acting genotype-environment interactions (GxE)-genetic effects on gene expression that depend on an environmental condition. Treating 17 common, clinical traits as approximations of the cellular environment of 267 skeletal muscle biopsies, we identify 10 candidate environmental response expression quantitative trait loci (reQTLs) across 6 traits (12 unique gene-environment trait pairs; 10% FDR per trait) including sex, systolic blood pressure, and low-density lipoprotein cholesterol. Although using ASE is in principle a promising approach to detect GxE effects, replication of such signals can be challenging as validation requires harmonization of environmental traits across cohorts and a sufficient sampling of heterozygotes for a transcribed SNP. Comprehensive discovery and replication will require large human transcriptome datasets, or the integration of multiple transcribed SNPs, coupled with standardized clinical phenotyping.