Genetic Regulation of DNA Methylation and Its Mediating Role in Blood Pressure: A Genome-Wide Twin Study

DNA methylation regulates gene expression, yet its role in the genetic regulation of blood pressure (BP) remains unclear. Using 1056 Chinese National Twin Registry participants (528 twin pairs), we estimated genome-wide DNA methylation heritability and genetic correlations between DNA methylation and BP using structural equation models. Genetically correlated CpGs were then tested using linear mixed-effects models in the full sample and in monozygotic twin pairs. Mendelian randomization (MR) was applied using East Asian methylation quantitative trait locus (mQTL) and genome-wide association study (GWAS) data, followed by integration of cis-expression QTL and cis-protein QTL data and MR-based mediation analysis to examine whether upstream genes and proteins influence BP through DNA methylation. Genome-wide DNA methylation heritability averaged 18.3%, with modest genetic correlations between DNA methylation and BP (mean |r _A| = 0.08-0.09). Association analyses identified 914 and 624 CpGs for systolic and diastolic BP, respectively, with substantial attenuation in monozygotic within-pair analyses, suggesting predominant genetic influences. Bidirectional relationships were identified between six CpGs and BP. MR-based mediation estimates suggested that methylation at specific sites may mediate 34%-93% of upstream gene/protein effects on BP, implicating HBEGF, CARD9, XCL1, and PCOLCE. These findings highlight DNA methylation as a potentially important regulatory layer in genetically influenced BP pathways.