Fine mapping of GWAS signals to identify genetic markers of the plasma triglyceride response to an omega-3 fatty acid supplementation

Background: Using a genome-wide association study (GWAS) approach, our group previously computed a genetic risk score (GRS) from single nucleotide polymorphisms (SNPs) of ten loci which affect the plasma triglyceride (TG) response to an omega-3 (n-3) fatty acid (FA) supplementation. Objective: The objective was to compute a novel and more refined GRS using fine mapping to include a large number of genetic variants. Design: A total of 208 participants of the Fatty Acid Sensor (FAS) study received 5g of fish oil per day, containing 1.9–2.2g of eicosapentanoic acid and 1.1g of docosahexanoic acid, for six weeks. Plasma TG levels were measured before and after supplementation. Dense genotyping and genotype imputation were employed to refine mapping around GWAS hits. A GRS was computed by summing the number of at-risk alleles of tagging SNPs. Analyses were replicated in samples of the FINGEN study. Results: A total of 31 tagging SNPs associated with the TG response were used for GRS calculation in the FAS study. In a general linear model adjusted for age, sex and body mass index, the GRS explained 49.73% of TG response variance (p < 0.0001). Non-responders to the n-3 FA supplementation had a higher GRS than responders. In the FINGEN replication study, the GRS explained 3.67% of TG response variance (p = 0.0006). Conclusion: Fine mapping proved to be effective to refine the previous GRS. Carrying increasing numbers of at-risk alleles of 31 SNPs confers a higher risk of being non-responsive to n-3 FA. The genetic profile therefore appears to be an important determinant of the plasma TG response to an n-3 FA supplementation and could be used to target those most likely to gain clinical benefit.