Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: A cross-sectional gene–diet interaction study

BACKGROUND AND AIMS: Several genetic variants have been identified to modify the effects of fish oil supplementation (FOS) on increasing circulating omega-3 fatty acids, but it remains unexplored whether polygenic predisposition to low circulating omega-3 fatty acids modifies these effects. This study aims to test if polygenic scores (PGS) for circulating omega-3 fatty acids modify the associations of FOS with corresponding circulating concentrations. METHODS: We developed PGS models for absolute circulating concentrations of total omega-3 fatty acids (Omega-3), docosahexaenoic acid (DHA), and their relative percentages in total fatty acids (Omega-3% and DHA%), using a multi-ethnic genome-wide association study (N = 136,016). PGS models were validated in 437,803 participants of European (EUR), Central/South Asian (CSA), African, and East Asian genetic ancestries. Linear models tested PGS-by-FOS interactions on corresponding observed circulating concentrations. Discovery analysis was performed separately in 237,380 EUR participants and each non-EUR group. Replication analyses were performed using two secondary exposures (i.e., oily fish intake and dietary omega-3 intake) and in another 178,935 EUR participants. These interaction patterns were consistently observed in the CSA ancestry and confirmed in replication and sensitivity analyses. CONCLUSIONS: PGS modify the associations of FOS with circulating omega-3 fatty acids in EUR and CSA populations, with larger FOS effects in participants with lower PGS. These findings support the development of genome-informed precision nutrition.