A multi-level gene-diet interaction analysis of fish oil supplementation and 14 circulating polyunsaturated fatty acids-related traits identifies the FADS and GRP12 loci

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) among individuals but in a heterogeneous manner. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs ( P < 5 × 10 ⁻⁸ ) in the FADS1-FADS2 gene cluster for total omega-3, omega-3%, docosapentaenoic acid (DHA), DHA% and the omega-6 to omega-3 ratio. Among the interaction signals for omega-3%, the lead SNP, rs35473591 (C>CT, CT allele frequency = 0.34), had a lower association effect size in the FOS-taking group (β = 0.35 for allele C) than that in the group without FOS (β = 0.42). Likewise, the effect sizes of associations between FOS and omega-3% varied across the three genotype groups (β = 0.45, 0.50, and 0.59, respectively, in C/C, C/CT, and CT/CT). Our gene-level aggregate and transcriptome-wide interaction analyses identified significant signals at two loci, around FADS1-FADS2 and GRP12 . The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systemic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations.