We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57–67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10⁻⁷), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = −1.71, p = 4 x 10⁻⁸) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.

中文翻译：

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线粒体基因组拷贝数的表观基因组关联研究

我们对五个队列（n  = 6182，平均年龄 57-67 岁，65% 女性）。在对所有参与者的荟萃分析中，我们发现了 21 个 mtDNA CN 相关的 CpG 位点 ( p  < 1 x 10 ^-7 )，mtDNA CN 的标准差增加（3 个 CpGs）或减少（18 个 CpGs）为 0.7 至 3.0 标准差对应于 DNA 甲基化增加 1%。据报道，一些重要的 CpG 与心血管疾病 (CVD) 的至少两个危险因素（例如实际年龄或吸烟）有关。五个基因（PRDM16、NR1H3、XRCC3、POLK和PDSS2）含有九个重要的 CpG，已知参与线粒体生物合成和功能。例如，NR1H3编码的转录因子在脂肪组织转化过程中表达差异。NR1H3 中cg09548275的甲基化水平与 mtDNA CN 呈负相关（效应大小 = -1.71，p  = 4 x 10 ^-8），与NR1H3表达水平呈正相关（效应大小 = 0.43，p  = 0.0003），这表明NR1H3甲基化水平可能是 mtDNA CN、NR1H3 转录因子和能量消耗之间关系的基础。总之，研究结果表明，全血中的 mtDNA CN 变异与参与多种线粒体活动的基因中的 DNA 甲基化水平相关。这些发现将有助于揭示 mtDNA CN 和 CVD 之间的分子机制。