Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease

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.

Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease

“…A wide range of studies suggest the genetic and pathological links between AD and T2D/obesity [17,40,41]. DNA methylation plays an important regulatory role in the pathogenesis of T2D, obesity and AD [11,14]. In addition, our study identi ed that AD and T2D/obesity share several common genetic and epigenetic architectures.…”

“…DNA methylation of CpGs is strongly associated with genetic loci, might explaining additional phenotypic variation in diseases besides genetic variants. Thus DNA methylation was considered as IVs (or intermediate phenotype) in a wide range of MR studies to infer the causal association between DNA methylation and complex diseases [11,12,14,15], bridging the GWAS gap regarding SNPs to diseases. Therefore, we explored the casual DNA methylation for metabolic traits and AD with the cis-mQTLs determined DNA methylation as IVs.…”

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption

“…In addition, we assessed the potential causal association of coffee-related CpGs with a number of cardiovascular and metabolic traits, including coronary heart disease (CHD), type 2 diabetes (T2D), BMI, waist-hip ratio (WHR), lipid traits (HDL-C, LDL-C, total cholesterol, triglycerides), and fatty liver disease. For each CpG, we calculated instrumental variables for DNA methylation levels based on methylation quantitative trait loci (cis-meQTL) obtained from FHS cohort (N~4,170) 44 . Two methods were used to explore causality.…”

Thioredoxin‐interacting protein promotes activation and inflammation of monocytes with DNA demethylation in coronary artery disease

“…Because epigenetic processes are reversible, they are potentially valuable targets for disease treatment . Therefore, continuous explorations of the relationship between epigenetic mechanisms in the plaque formation and rupture will provide novel insights into the aetiology and potential therapeutic targets …”

“…8 Therefore, continuous explorations of the relationship between epigenetic mechanisms in the plaque formation and rupture will provide novel insights into the aetiology and potential therapeutic targets. 9 Coronary artery disease was considered to be caused by a series of inflammatory procedures and promoted by oxidative stress. 10,11 The imbalance in the oxidant/antioxidant mechanisms caused by excessive reactive oxygen species (ROS) leads to a state of oxidative stress.…”