Abstract
DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.
Highlights
DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear
To identify the biological processes that may be related to these 98 pQTMs, we characterized the implicated CpG sites and proteins using additional data sets: Using the BIOS QTL server[5] we identified 18 expression QTMs that overlapped with the 89 unique CpG sites
We have carried out a large epigenome-wide association study with proteomics data
Summary
DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Complex networks of (co-)associated multi-omics traits, connecting CpG methylation, gene expression, protein, and metabolite levels to disease endpoints emerge from such EWASs, as we recently showed at the example of a multi-omics association study with a small set of CpG sites[15]. Such networks might eventually guide a more personalized treatment of complex disorders, using for instance DNA methylation as a precise readout of the body’s disease status with respect to the affected pathways, or to identify drug targets that may allow the modification of the underlying dysregulated processes. 450K array (Illumina Inc.) in samples from 944 individuals of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study[16] and from 344 participants of the Metabolites
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