Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: A cross-sectional gene-diet interaction study.
Polygenic scores (PGS) for circulating omega-3 fatty acids significantly modify the associations of fish oil supplementation with corresponding circulating concentrations, with larger supplementation effects observed in participants with lower PGS, supporting genome-informed precision nutrition.
Key Findings
Results
PGS models for circulating omega-3 fatty acids explained 5.3–11.1% of phenotypic variance in European ancestry participants.
PGS were developed for four traits: absolute total omega-3 (Omega-3), DHA, and their relative percentages (Omega-3% and DHA%).
Models were built using a multi-ethnic GWAS with N = 136,016 participants.
Validation was performed in 437,803 participants across European (EUR), Central/South Asian (CSA), African, and East Asian genetic ancestries.
Discovery analysis was conducted separately in 237,380 EUR participants and each non-EUR ancestry group.
Results
Significant PGS-by-fish oil supplementation interactions were detected across all four circulating omega-3 traits in European ancestry participants.
Interaction p-values were statistically significant for all four traits (Omega-3, DHA, Omega-3%, DHA%).
The interaction for total Omega-3 reached PInt = 4.03 × 10⁻¹⁰ when comparing top and bottom 5% of PGS distribution.
For the population average, fish oil supplementation (FOS) was associated with a β = 0.36 SD increase in Omega-3 (95% CI: 0.35–0.37).
PInt for the population-level interaction analysis was 0.016.
Results
Participants in the bottom 5% of the PGS distribution showed a significantly larger association of fish oil supplementation with circulating total omega-3 compared to the population average.
The pattern of larger fish oil supplementation effects in lower-PGS individuals was consistently observed in Central/South Asian ancestry participants.
Interaction patterns observed in EUR participants were replicated in the CSA ancestry group.
Results were also confirmed in replication and sensitivity analyses.
Non-EUR groups included African and East Asian ancestries in addition to CSA, though consistent interactions were specifically noted for CSA.
Results
Replication analyses using oily fish intake and dietary omega-3 intake as secondary exposures confirmed the PGS interaction findings.
Two secondary exposures were used for replication: oily fish intake and dietary omega-3 intake.
Replication was also performed in a separate sample of 178,935 EUR participants.
Interaction patterns were confirmed across these replication analyses.
This suggests findings are robust across different sources of omega-3 intake, not only supplementation.
Methods
The study developed polygenic scores using a multi-ethnic genome-wide association study approach to improve cross-ancestry applicability.
The GWAS used for PGS development included N = 136,016 participants from multiple ethnic backgrounds.
PGS were validated across four ancestry groups: European, Central/South Asian, African, and East Asian.
The multi-ethnic design was intended to support broader applicability of genome-informed precision nutrition findings.
What This Means
This research suggests that a person's genetic makeup influences how much their omega-3 blood levels rise when they take fish oil supplements. Scientists created 'polygenic scores' (PGS) — tools that summarize the combined effect of many genetic variants — to predict how likely someone is to naturally have low circulating omega-3 fatty acids. They then tested whether these scores could predict who benefits most from fish oil supplementation, using data from hundreds of thousands of people across multiple ethnic backgrounds.
The key finding is that people with genetic profiles associated with naturally lower omega-3 levels (low PGS) showed the largest increases in blood omega-3 when taking fish oil supplements. Specifically, those in the bottom 5% of the genetic score distribution saw about 43% greater increases in circulating omega-3 compared to those in the top 5%. This pattern held up across different ancestries (particularly in European and Central/South Asian populations) and was also seen with other omega-3 sources like eating oily fish.
This research suggests that genetic testing could eventually help identify which individuals are most likely to benefit from fish oil supplementation or increased omega-3 intake — a concept known as 'precision nutrition.' People who are genetically predisposed to lower omega-3 levels may respond more strongly to supplementation, while those with a genetic tendency toward higher omega-3 levels may see smaller effects. The findings add to growing evidence that personalized dietary recommendations based on genetics could be more effective than one-size-fits-all nutritional advice.
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Xu H, Yu G, Lu Y, Fuller H, Song S, Shen Y, et al.. (2026). Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: A cross-sectional gene-diet interaction study.. Clinical nutrition (Edinburgh, Scotland). https://doi.org/10.1016/j.clnu.2026.106774