Systematic Mendelian randomization framework elucidates hundreds of CpG sites which may mediate the influence of genetic variants on disease

Abstract

We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P < 1.39 × 10−08). Joint likelihood mapping provided evidence that the genetic variant which influenced DNA methylation levels for 348 of these associations across 47 traits was also responsible for variation in complex traits. These associations showed a high rate of replication in the BIOS QTL and UK Biobank datasets for 14 selected traits, as 101 of the attempted 128 associations survived multiple testing corrections (P < 3.91 × 10−04). Integrating expression quantitative trait loci (eQTL) data suggested that genetic variants responsible for 306 of the 348 refined meQTL associations also influence gene expression, which indicates a coordinated system of effects that are consistent with causality. CpG sites were enriched for histone mark peaks in tissue types relevant to their associated trait and implicated genes were enriched across relevant biological pathways. Though we are unable to distinguish mediation from horizontal pleiotropy in these analyses, our findings should prove valuable in prioritizing candidate loci where DNA methylation may influence traits and help develop mechanistic insight into the aetiology of complex disease.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

“…In addition, our study improved upon some previous MR studies of omics 7 8 by utilising both cis and trans instruments. Several of the approaches (single-cis, multi-cis and trans-only) yielded informative results.…”

“…Recent MR studies highlight the value of hypothesis-free (“phenome-wide”) MR in building a comprehensive picture of the causal effects of risk factors on disease outcomes 8 34 35 . Given that human proteins represent the major source of therapeutic targets, we sought to mine our results for targets of molecules already approved as treatments or in ongoing clinical development, and which might represent promising candidates for repositioning.…”

“…Thus, systematically evaluating the genetic evidence in support of potential target-indication pairs is a potential strategy to prioritise development programmes. However, whilst systematic genetic studies have evaluated the putative causal role of both methylome and transcriptome on diseases 7 8 , no systematic causal inference study has yet been conducted to evaluate the role of the proteome in disease.…”

IMAGE: High-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis

“…Nevertheless, in its current form, IMAGE is well-suited to analyzing sequencing-based DNA methylation data sets of the size and scale typically generated in recent studies [103]. Thus, it can be flexibly deployed to investigate the genetic architecture of gene regulatory variation, the relative role of genes and the environment in shaping the epigenome, or the mediating role of DNA methylation in linking environmental conditions to downstream phenotypes, including human disease (e.g., via Mendelian randomization or related approaches [104, 105]).…”

The DNA Methylome of Inflammatory Bowel Disease (IBD) reflects intrinsic and extrinsic factors in intestinal epithelial cells

“…Instead, they could be associated with other regulatory regions such as enhancers, for example in association with SNPs. Indeed, GWAS performed in multiple complex diseases have shown that SNPs of susceptibility are enriched in enhancer regions, and DNA methylation could be an intermediary in this process 31,32 . Illustrating this, the presence of differentially methylated sites in the vicinity of known susceptibility loci supports the notion of DNA methylation as an intermediary between genotype and phenotype (mQTLs).…”