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

Figures

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  FIGURE 1. Genome‐wide heritability of DNA methylation: (A) Distribution of the proportions of variance in DNA methylation explained by additive genetic (a 2) and unique environmental (e 2) components across all CpG sites under the full structural equation model. Vertical lines indicate mean values (n = 948); and (B) distribution of twin‐based heritability (h 2) estimates across all CpG sites from the best fitting model (n = 948). a 2, additive genetic variance component; e 2, unique environmental variance component; h 2, heritability.

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  FIGURE 2. Genome‐wide genetic and environmental correlations between DNA methylation and blood pressure: Distribution of genetic (red) and environmental (blue) correlations between individual CpG sites and (A) SBP and (B) DBP (n = 948). |r A|, genetic correlation; |r E|, environmental correlation; DBP, diastolic blood pressure; SBP, systolic blood pressure.

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  FIGURE 3. Manhattan plots of association analyses for blood pressure: Manhattan plots showing the association between DNA methylation at genetically correlated CpG sites and (A) SBP and (B) DBP (n = 1056). The x‐axis represents chromosomal position, and the y‐axis represents −log10(p value). The red line indicates the FDR < 0.05 threshold and the gray line indicates p < 1 × 10−5. DBP, diastolic blood pressure; FDR, false discovery rate; SBP, systolic blood pressure.

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  FIGURE 4. Bidirectional Mendelian randomization analyses between CpG sites and blood pressure: volcano plots showing MR estimates for (A) CpG → SBP, (B) CpG → DBP, (C) SBP → CpG, and (D) DBP → CpG. All tested associations are shown. Gray points indicate p ≥ 0.05, whereas red and blue points indicate nominally significant positive and negative associations, respectively. CpGs surviving FDR correction are labeled. The gray and red lines indicate p = 0.05 and FDR = 0.05, respectively. DBP, diastolic blood pressure; FDR, false discovery rate; SBP, systolic blood pressure.

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  FIGURE 5. Upstream genetic regulators of blood pressure‐associated CpG sites: volcano plots showing MR estimates for gene → CpG associations in (A) SBP‐related and (B) DBP‐related pathways. Red and blue points indicate nominally significant positive and negative associations, respectively. The gray and red lines indicate p = 0.05 and the threshold corresponding to FDR < 0.05, respectively. All tested gene–CpG associations are shown, with the 12 associations having the smallest p values in each panel labeled for readability. Network plots showing protein → CpG associations for (C) SBP‐related and (D) DBP‐related pathways. Circles and triangles represent proteins and CpGs, respectively, whereas red and blue arrows indicate positive and negative effects. DBP, diastolic blood pressure; SBP, systolic blood pressure.

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  FIGURE 6. Proportion of gene and protein effects on blood pressure mediated by DNA methylation. (A) eQTL‐based gene pathways. (B) pQT‐based protein pathways. Stacked bar charts showing the proportion of the total effect of upstream genes and proteins on blood pressure mediated through DNA methylation versus the remaining direct effect. Percentages on the right indicate the mediated proportion for each pathway. Only pathways in which the gene/protein → CpG and CpG → blood pressure effects were in a consistent direction are shown. DBP, diastolic blood pressure; eQTL, expression quantitative trait locus; pQTL, protein quantitative trait locus; SBP, systolic blood pressure.

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  FIGURE 7. Overview of the study design and analytical framework. BP, blood pressure; CNTR, Chinese National Twin Registry; DBP, diastolic blood pressure; eQTL, expression quantitative trait locus; FDR, false discovery rate; GWAS, genome‐wide association study; MR, Mendelian randomization; mQTL, methylation quantitative trait locus; MZ, monozygotic; pQTL, protein quantitative trait locus; SBP, systolic blood pressure; SEM, structural equation model.