Genome-wide search identified DNA methylation sites that regulate the metabolome

Background: Identifying DNA methylation sites that regulate the metabolome is important for several purposes. In this study, publicly available GWAS data were integrated to find methylation sites that impact metabolome through a discovery and replication scheme and by using Mendelian randomization.Results: The outcome of analyses revealed 107 methylation sites associated with 84 metabolites at the genome-wide significance level (p<5e(-8)) at both the discovery and replication stages. A large percentage of the observed associations (85%) were with lipids, significantly higher than expected (p = 0.0003). A number of CpG (methylation) sites showed specificity e.g., cg20133200 within PFKP was associated with glucose only and cg10760299 within GATM impacted the level of creatinine; in contrast, there were sites associated with numerous metabolites e.g., cg20102877 on the 2p23.3 region was associated with 39 metabolites. Integrating transcriptome data enabled identifying genes (N = 82) mediating the impact of methylation sites on the metabolome and cardiometabolic traits. For example, PABPC4 mediated the impact of cg15123755-HDL on type-2 diabetes. KCNK7 mediated the impact of cg21033440-lipids on hypertension. POC5, ILRUN, FDFT1, and NEIL2 mediated the impact of CpG sites on obesity through metabolic pathways.Conclusion: This study provides a catalog of DNA methylation sites that regulate the metabolome for downstream applications.

Automated summary

This study integrated GWAS data and used Mendelian randomization to identify 107 methylation sites associated with 84 metabolites. The majority of associations were with lipids, which was significantly higher than expected. The study also identified 82 genes that mediate the impact of methylation sites on metabolites and cardiometabolic traits.