Fig. 3: Association and meta-analyses of mtDNA heteroplasmy with DNA methylation.

A Cohort- and race-specific association analyses using linear regression were followed by meta-analyses in pooled samples (n = 10,986) to identify CpG sites associated with MSS (top) and MHC (bottom). We found 479 MSS- and 166 MHC-associated CpGs at a false discovery rate (FDR) < 0.05 in a two-sided test. The x-axis indicates chromosomes in different colors. The gray dotted line represents the FDR-adjusted significance threshold (FDR = 0.05), and the black dotted line indicates the Bonferroni threshold (p = 1 × 10^-7). B Comparison of effect sizes (beta values) for MSS vs. MHC meta-analyses, showing a Pearson correlation r of 0.75. Red dots indicate CpGs with positive betas and blue dots with negative betas. C Volcano plot of DNA methylation with MSS in meta-analysis. Most significant CpGs (94%, FDR < 0.05) showed negative associations (blue dots), while a minority showed positive associations (red points). D Forest plot of the top CpG, cg15233611, from linear regression analyses of MSS in African American (AA) and White American (EA) participants, and in the meta-analysis. All tests were two-sided t-tests. Among AA participants, beta-estimates (95% CI) were 0.00087 (–0.0097, 0.011) in ARIC, –0.0077 (–0.032, 0.016) in CARDIA, –0.018 (–0.038, 0.0021) in GENOA, –0.022 (–0.033, –0.0097) in JHS, 0.0059 (–0.027, 0.039) in MESA, and –0.021 (–0.066, 0.024) in WHI, with a meta-analysis estimate of –0.010 (–0.021, 0.00063) in all AA participants. For White American (EA) participants, the β (95% CI) values were –0.0087 (–0.022, 0.0041) in ARIC, –0.0094 (–0.031, 0.012) in CARDIA, –0.015 (–0.021, –0.0092) in FHS, –0.013 (–0.035, 0.0086) in MESA, and –0.039 (–0.058, –0.0019) in WHI. The meta-analysis of EA participants yielded a beta of −0.015 (–0.020, –0.010), and the overall meta-analysis combining AA and EA participants produced a beta of –0.014 (–0.019, –0.0099). CI confidence interval, ARIC Atherosclerosis Risk in Communities, CARDIA Coronary Artery Risk Development in Young Adults, FHS Framingham Heart Study, GENOA Genetic Epidemiology Network of Arteriopathy, JHS Jackson Heart Study, MESA Multi-Ethnic Study of Atherosclerosis Study, WHI Women’s Health Initiative.