Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers

• Published in: Nature communications Vol. 13; no. 1; pp. 3993 - 11
• Main Authors: Westerman, Kenneth E, Majarian, Timothy D, Giulianini, Franco, Jang, Dong-Keun, Miao, Jenkai, Florez, Jose C, Chen, Han, Chasman, Daniel I, Udler, Miriam S, Manning, Alisa K, Cole, Joanne B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.07.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alcohol dehydrogenase; Biomarkers; Body fat; Body mass; Cardiovascular Diseases - genetics; Computer applications; Environmental factors; Exposure; Female; Gene mapping; Gene-Environment Interaction; Genetic diversity; Genetic effects; Genetic variance; Genome-Wide Association Study; Genomes; Genotype; Genotypes; Humans; Phenotype; Phenotypic variations; Polymorphism, Single Nucleotide; Precision medicine; Quantitative trait loci; Quantitative Trait Loci - genetics; Triglycerides; Variance analysis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31625-5

Gene-environment interactions represent the modification of genetic effects by environmental exposures and are critical for understanding disease and informing personalized medicine. These often induce differential phenotypic variance across genotypes; these variance-quantitative trait loci can be prioritized in a two-stage interaction detection strategy to greatly reduce the computational and statistical burden and enable testing of a broader range of exposures. We perform genome-wide variance-quantitative trait locus analysis for 20 serum cardiometabolic biomarkers by multi-ancestry meta-analysis of 350,016 unrelated participants in the UK Biobank, identifying 182 independent locus-biomarker pairs (p < 4.5×10 ). Most are concentrated in a small subset (4%) of loci with genome-wide significant main effects, and 44% replicate (p < 0.05) in the Women's Genome Health Study (N = 23,294). Next, we test each locus-biomarker pair for interaction across 2380 exposures, identifying 847 significant interactions (p < 2.4×10 ), of which 132 are independent (p < 0.05) after accounting for correlation between exposures. Specific examples demonstrate interaction of triglyceride-associated variants with distinct body mass- versus body fat-related exposures as well as genotype-specific associations between alcohol consumption and liver stress at the ADH1B gene. Our catalog of variance-quantitative trait loci and gene-environment interactions is publicly available in an online portal.