PT - JOURNAL ARTICLE AU - Tom G. Richardson AU - Jie Zheng AU - George Davey Smith AU - Nicholas J. Timpson AU - Tom R. Gaunt AU - Caroline L. Relton AU - Gibran Hemani TI - Causal epigenome-wide association study identifies CpG sites that influence cardiovascular disease risk AID - 10.1101/132019 DP - 2017 Jan 01 TA - bioRxiv PG - 132019 4099 - http://biorxiv.org/content/early/2017/04/29/132019.short 4100 - http://biorxiv.org/content/early/2017/04/29/132019.full AB - The extent to which genetic influences on complex traits and disease 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 < 3.83×10-08). Bivariate fine mapping suggested that the individual variants responsible for the observed effects on cardiovascular traits at the ABO, ADCY3, ADIPOQ, APOA1 and IL6R loci were likely mediated through changes in DNA methylation. Causal effect estimates on cardiovascular traits ranged between 0.109-0.992 per standard deviation change in DNA methylation and were replicated using results from large-scale consortia.Functional informatics suggests that the causal variants and CpG sites identified in this study were enriched for histone mark peaks in adipose tissue 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.