# A multi-level gene-diet interaction analysis of fish oil and 14 polyunsaturated fatty acid traits identifies the FADS and GPR12 loci

## TL;DR

This study finds that genetic differences affect how people respond to fish oil supplements, influencing levels of important fatty acids in the blood.

## Contribution

The study identifies two genetic loci, FADS1-FADS2 and GPR12, that modify the effects of fish oil on fatty acid levels.

## Key findings

- Genome-wide significant SNPs were found in the FADS1-FADS2 gene cluster for several PUFA traits.
- Effect sizes of fish oil on omega-3% varied significantly across different genotype groups.
- Gene-FOS interactions significantly contribute to phenotypic variance in omega-3-related traits.

## Abstract

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. 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 GPR12. The contribution of genome-wide gene-FOS interactions to phenotypic variance was statistically significant in omega-3-related traits. This systematic gene-FOS GWIS contributes to our understanding of the genetic architecture of circulating PUFAs underlying FOS response and informs personalized dietary recommendations.

A multi-level genome-wide interaction study in 200,060 UK Biobank participants identified two loci around FADS1-FADS2 and GPR12 whose genotypes modify the associations of fish oil supplementation with the circulating levels of polyunsaturated fatty acids. Individuals with different genotypes need different doses of fish oil to achieve the same circulating levels.