Systematic evaluation of the causal relationship between DNA methylation and C-reactive protein

Abstract

House; Bristol BS8 2BN; esther.walton@bristol.ac.uk; phone: +44 (0) 117 3314026; fax: +44 (0) 117 3314052. AbstractElevated C-reactive protein (CRP) levels are an indicator of chronic low-grade inflammation.Epigenetic modifications, including DNA methylation, have been linked to CRP, but systematic investigations into potential underlying causal relationships have not yet been performed.We systematically performed two-sample Mendelian randomization and colocalization analysis between CRP and DNA methylation levels, using GWAS and EWAS summary statistics as well as individual level data available through the ARIES subset of the Avon Longitudinal Study of Parents and Children (ALSPAC; 1,616 participants).We found no convincing examples for a causal association from CRP to DNA methylation.Testing for the reverse (a putative causal effect of DNA methylation on CRP), we found three CpG sites that had shared genetic effects with CRP levels after correcting for multiple testing (cg26470501 (offspring: beta=0.07 [0.03, 0.11]; mothers: beta=0.08 [0.04, 0.13]), cg27023597 (offspring: beta=0.18 [0.10, 0.25]; mothers: beta=0.20 [0.12, 0.28]) and cg12054453 (offspring: beta=0.09 [0.05, 0.13])) influenced CRP levels. For all three CpG sites, linked to the genes TMEM49, BCL3 and MIR21, increased methylation related to an increase in CRP levels. Two CpGs (cg27023597 and cg12054453) were influenced by SNPs in genomic regions that had not previously been implicated in CRP GWASs, implicating them as novel genetic associations.Overall, our findings suggest that CRP associations with DNA methylation are more likely to be driven by either confounding or causal influences of DNA methylation on CRP levels, rather than the reverse.

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

“…While the DNAm CRP score may be capturing a more reliable picture of inflammation than measured CRP, it would be desirable to investigate its relationship with a panel of inflammatory mediators and to create epigenetic scores of other inflammatory biomarkers to test their comparative performance. Finally, no causal analysis was conducted in this study, so it remains to be determined (a) if CRP has a direct effect on methylation or indeed the opposite is true, though this has begun to be addressed elsewhere [25,57]; and (b) if inflammation-related DNAm is causal of poorer cognition, vice-versa, or both are influenced by a confounding factor.…”

Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

“…Additionally, a chronic signature of inflammation might manifest in whole blood through changes in cell type proportions which should also be considered moving forward. Finally, no causal analysis was conducted in this study so it remains to be determined a) if CRP has a direct effect on methylation or indeed the opposite is true, though this has begun to be addressed elsewhere (25, 48); and b) if inflammation-related DNA methylation is causal of poorer cognition, vice-versa, or both are influenced by a confounding factor.…”

Using Openly Accessible Resources to Strengthen Causal Inference in Epigenetic Epidemiology of Neurodevelopment and Mental Health

“…Depending on the research question, the sample characteristics and data availability, different MR methodologies can be applied, such as one-sample, two-sample, bidirectional, multivariable and two-step MR, the details of which can be found elsewhere [43,44]. Due to limitations in data availability and the computational resources required, MR has predominantly been performed to date on selected methylation loci (e.g., top hits of a robust EWAS), with a few notable exceptions [45,46]. However, with the advent of more detailed data on genetic variants that tag methylation variation, the approach promises to be more widely adopted.…”