AUTHOR=Nikpay Majid 

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

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1093882

DOI=10.3389/fgene.2023.1093882

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Results:</bold> The outcome of analyses revealed 107 methylation sites associated with 84 metabolites at the genome-wide significance level (<italic>p</italic>&lt;5e<sup>−8</sup>) at both the discovery and replication stages. A large percentage of the observed associations (85%) were with lipids, significantly higher than expected (<italic>p</italic> = 0.0003). A number of CpG (methylation) sites showed specificity e.g., cg20133200 within <italic>PFKP</italic> was associated with glucose only and cg10760299 within <italic>GATM</italic> 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, <italic>PABPC4</italic> mediated the impact of cg15123755-HDL on type-2 diabetes. <italic>KCNK7</italic> mediated the impact of cg21033440-lipids on hypertension. <italic>POC5, ILRUN, FDFT1,</italic> and <italic>NEIL2</italic> mediated the impact of CpG sites on obesity through metabolic pathways.</p><p><bold>Conclusion:</bold> This study provides a catalog of DNA methylation sites that regulate the metabolome for downstream applications.</p>