Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk

The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits.

We identified 10 genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits (P < 3.83 x 10^-08). Bivariate fine mapping identified strong evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, whereas the other loci require further evaluation, though we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Causal effect estimates ranged between 0.109-0.992 cardiovascular trait units per standard deviation change in DNA methylation and were replicated using results from large-scale consortia.

Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data we provide evidence that variation at these regulatory regions is likely to also influence gene expression at these loci.