Gene–Diet Interaction Analysis in UK Biobank Identified Genetic Loci That Modify the Association Between Fish Oil Supplementation and the Incidence of Dementia

Background

Dementia is a common disease influenced by both genetic and environmental factors. APOE ε4 is well-known to increase risk of dementia, and it has been shown to attenuate the protective association of fish oil supplements (FOS) and the incidence of dementia.

Objectives

To identify additional genetic factors with modifying effects, we performed a genome-wide scan.

Methods

We performed genome-wide association studies (GWAS) of incident all-cause dementia, Alzheimer's disease, and vascular dementia in 357,631 participants from UK Biobank and the FOS subgroups. Single-nucleotide polymorphisms (SNPs) suggestively associated with dementia (P < 1 × 10⁻⁵) were then evaluated for their interactions with fish oil status in Cox regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals.

Results

Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (P < 5 × 10⁻⁸) for the incidence of all-cause dementia, Alzheimer's disease, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for Alzheimer's disease and related dementia. A total of 178 suggestive GWAS loci (P < 1 × 10⁻⁵) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between FOS and dementia incidence (P < 2.8 × 10⁻⁴ with Bonferroni correction). One locus overlapped with a known Alzheimer's disease GWAS locus (EED/PICALM) and 2 with GWAS loci for circulating ω-3 fatty acids (SRSF4 and PSMG1). Candidate interacting genes exhibited cell-type–specific expression in the nervous system.

Conclusions

In total, 43 genetic loci modify the association between FOS and dementia. These findings indicate a need for genome-informed personalized nutrition of FOS for the purpose of dementia prevention.