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Abstract
Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.
Highlights
Identifying methylation quantitative trait loci and integrating them with diseaseassociated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations
By overlapping independent cis-meQTL single nucleotide polymorphisms (SNPs) with results from GWAS of cardiovascular disease (CVD) and its risk factors[21,22,23,24,25], we identified 14,910 CpGs, each of which has at least three independent cismeQTL SNPs that were suitable instruments for Mendelian randomization (MR) to test for causal effects of DNA methylation (DNAm) on coronary heart disease (CHD)[21], myocardial infarction (MI)[21], type-II diabetes (T2D)[22], systolic (SBP) and diastolic blood pressure (DBP)[25], and 9921 CpGs suitable to test causality of DNAm on lipids traits including highdensity lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol (TC), triglycerides (TG)[24], and body mass index (BMI)[23]
Among the 12 putatively casual CpGs for CHD and MI, we found five CpGs that were positively associated with CHD/MI risk, and seven CpGs inversely associated with CHD/MI risk
Summary
Identifying methylation quantitative trait loci (meQTLs) and integrating them with diseaseassociated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. We hypothesized that identifying meQTL variants and linking them to disease-associated genetic variants from GWAS would pinpoint molecular mechanisms underlying genetic susceptibility to human diseases that are due, at least in part, to altered epigenetic regulation It could help explain the molecular consequences of non-protein-coding, diseaseassociated genetic variants from GWAS. To this end, we perform genome-wide association testing of genetic variants with whole blood DNAm from 4170 European ancestry (EA) participants in the Framingham Heart Study (FHS) and comprehensively map cis- and trans-meQTLs. External replication is performed in 963 EA participants in the Atherosclerosis Risk in Communities (ARIC) study and 384 AfricanAmerican ancestry (AA) participants in the Grady Trauma Project (GTP). We report trans-meQTL hotspots, each targeting 30 or more CpGs and demonstrate their influence on cis transcriptional regulatory genes
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