Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium

Abstract

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Figure 1. N-3 polyunsaturated fatty acid metabolic pathway and summary of genome-wide associations in pathway.

The fatty acids indicated in bold were examined in this study. The genome-wide significant associations of two loci with each fatty acid are shown with dashed arrows. + and − signs indicate the direction of the associations.

Figure 2. Meta-analysis of genome-wide associations with n-3 polyunsaturated fatty acids.

A: α-linolenic acid (ALA), B: eicosapentaenoic acid (EPA), C: docosapentaenoic acid (DPA), D: docosahexaenoic acid (DHA). Associations were graphed by chromosome position and –log₁₀ (p-value) up to p-values of 10⁻¹⁰. Triangles indicate additional SNPs with p-values less than 10⁻¹⁰. Genes of interest in the regions with significantly associated SNP variants are indicated.

Figure 3. SNP association plots for EPA–associated regions.

Genome-wide association significance level is plotted against the y-axis as –log₁₀ (p-value). Genetic coordinates are as per NCI build 36. A) FADS cluster region. LD is indicated by color scale in relationship to marker rs174538. B) ELOVL2 region. LD is indicated by color scale in relationship to marker rs3798713. The color scheme is red for strong linkage disequilibrium (LD; r²≥0.8) and fading color for lower LD.

Figure 4. SNP association plots for DPA–associated regions.

Genome-wide association significance level is plotted against the y-axis as –log₁₀ (p-value). Genetic coordinates are as per NCBI build 36. A) GCKR region. LD is indicated by color scale in relationship to marker rs780094. B) AGPAT3 region. LD is indicated by color scale in relationship to marker rs7435. The color scheme is red for strong linkage disequilibrium (LD; r²≥0.8) and fading color for lower LD.

Figure 5. Influence of variation in rs1535 on the estimated association of plasma phospholipid ALA levels with EPA levels.

Panel A illustrates the association of ALA with EPA in carriers of 0, 1, and 2 copies of rs1535 G allele with fitted lines constructed from meta-analyzed estimates. Panel B shows the % change in EPA corresponding to a 0.05 unit increase in ALA in carriers of 0 (top estimate), 1 (middle estimate), 2 (bottom estimate) copies of rs1535 G allele.