Abstract
BackgroundGenome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability.ResultsParent-of-origin (POO) effect association analyses using an agnostic approach or a candidate approach were performed for pretreatment TG levels, posttreatment TG levels, and pre- and posttreatment TG-level differences in the real GAW20 family data set. We detected 22 genetic variants with suggestive POO effects with at least 1 phenotype (P ≤ 10− 5). We evaluated the association of these 22 significant genetic variants showing POO effects with close DNA methylation probes associated with TGs. A total of 18 DNA methylation probes located in the vicinity of the 22 SNPs were associated with at least 1 phenotype and 6 SNP-probe pairs were associated with DNA methylation probes at the nominal level of P < 0.05, among which 1 pair presented evidence of POO effect. Our analyses identified a paternal effect of SNP rs301621 on the difference between pre- and posttreatment TG levels (P = 1.2 × 10− 5). This same SNP showed evidence for a maternal effect on methylation levels of a nearby probe (cg10206250; P = 0.01). Using a causal inference test we established that the observed POO effect of rs301621 was not mediated by DNA methylation at cg10206250.ConclusionsWe performed POO effect association analyses of SNPs with TGs, as well as association analyses of SNPs with DNA methylation probes. These analyses, which were followed by a causal inference test, established that the paternal effect at the SNP rs301621 is induced by treatment and is not mediated by methylation level at cg10206250.
Highlights
Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability
Among the Single nucleotide polymorphism (SNP) previously reported to be associated with TG level, only 8 were associated with the phenotypes (TG1–2) at P ≤ 10− 3 and no SNP showed strong POO effects (P > 10− 3)
We identified 18 DNA methylation probes located in the vicinity of these SNPs that were associated with the phenotypes at P < 0.05 (11 with TG2, 3 with TG4, and 4 with ΔTG2–4)
Summary
Genome-wide association studies performed on triglycerides (TGs) have not accounted for epigenetic mechanisms that may partially explain trait heritability. Genetic studies have largely focused on DNA sequence variations Sources of this unexplained heritability might include epigenetic mechanisms such as DNA methylation. DNA methylation can cause partial or complete silencing of 1 parental allele at a specific locus and can lead to a differential effect of that polymorphism on disease in offspring according to the parental origin of the risk allele (parent-of-origin [POO] effect). Such epigenetic mechanism has been described for lipid levels by Predazzi et al, who reported sex-specific parental effects on offspring lipid levels [7]
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