A variance QTL approach to uncover gene-fish oil supplement interaction loci for 14 circulating unsaturated fatty acid traits.

Gene-environment interactions (GEIs) contribute to circulating polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) profiles. GEIs may partly explain differences in trait variance across genotype groups. To identify GEIs for circulating unsaturated fatty acids, we adopted a two-stage strategy. First, we detected quantitative trait loci associated with trait variance (vQTLs). Second, we tested these vQTLs for interaction with fish oil supplements (FOS). We performed genome-wide vQTL screens for 14 plasma PUFA and MUFA phenotypes in a UK Biobank subset of up to 200,736 participants. At the genome-wide significance threshold (p < 5.0 x 10-8), we identified 172 vQTL-trait pairs across all 14 traits, and 16 of these vQTLs had no marginal genetic effect on the corresponding trait. We found 46 non-overlapping loci across all phenotypes, with an average of 12 vQTLs per trait. Omega-6% and PUFA% had the most independent vQTLs (N = 24) while DHA% and Omega-3% had the least (N = 1 and 2, respectively). For each of the 172 vQTL-trait pairs, we tested the interaction effect of the vQTL with FOS on the corresponding trait. We found six significant interaction signals in DHA, DHA%, Omega-3, Omega-3%, LA, and Omega-6/Omega-3 ratio, mapping to the FADS1/2 locus and the ZPR1 and SUGP1/TM6SF2 genes, two additional loci not detected in our prior genome-wide interaction scan. Our results provide a comprehensive resource of vQTLs and gene-FOS interactions shaping the circulating levels of unsaturated fatty acids.