We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in 6745 maternal pairs of European (EA, n = 4718 pairs) and African (AA, n = 2027 pairs) Americans in whole blood. Mother-offspring pairs displayed the highest concordance rate, followed by sibling-sibling and more distantly-related maternal pairs. The allele fractions of concordant heteroplasmies exhibited high correlation (R² = 0.8) between paired individuals. Discordant heteroplasmies were more likely to be in coding regions, be nonsynonymous or nonsynonymous-deleterious (p < 0.001). The number of deleterious heteroplasmies was significantly correlated with advancing age (20–44, 45–64, and ≥65 years, p-trend = 0.01). One standard deviation increase in heteroplasmic burden (i.e., the number of heteroplasmies carried by an individual) was associated with 0.17 to 0.26 (p < 1e − 23) standard deviation decrease in mtDNA copy number, independent of age. White blood cell count and differential count jointly explained 0.5% to 1.3% (p ≤ 0.001) variance in heteroplasmic burden. A genome-wide association and meta-analysis identified a region at 11p11.12 (top signal rs779031139, p = 2.0e − 18, minor allele frequency = 0.38) associated with the heteroplasmic burden. However, the 11p11.12 region is adjacent to a nuclear mitochondrial DNA (NUMT) corresponding to a 542 bp area of the D-loop. This region was no longer significant after excluding heteroplasmies within the 542 bp from the heteroplasmic burden. The discovery that blood mtDNA heteroplasmies were both inherited and somatic origins and that an increase in heteroplasmic burden was strongly associated with a decrease in average number of mtDNA copy number in blood are important findings to be considered in association studies of mtDNA with disease traits.

我们调查了 6745 对欧洲人（EA，n = 4718 对）和非洲人（AA，n = 2027 对）美国人全血中线粒体 DNA 异质性突变（异质性）的一致性。母亲-后代对显示出最高的一致性率，其次是兄弟姐妹-兄弟姐妹和关系更远的母亲对。一致异质性的等位基因分数表现出高度相关性（R ² = 0.8) 配对个体之间。不一致的异质性更有可能位于编码区，是非同义的或非同义的-有害的 (p < 0.001)。有害异质性的数量与年龄增长显着相关（20-44、45-64 和≥65 岁，p 趋势 = 0.01）。异质性负担的一个标准差增加（即个体携带的异质性数量）与 mtDNA 拷贝数的 0.17 至 0.26 (p < 1e − 23) 标准差减少相关，与年龄无关。白细胞计数和分类计数共同解释了异质性负荷中 0.5% 至 1.3% (p ≤ 0.001) 的差异。全基因组关联和荟萃分析确定了 11p11.12 处的一个区域（顶部信号 rs779031139，p = 2.0e − 18，次要等位基因频率 = 0.38）与异质性负荷相关。然而，11p11.12 区域与对应于 D 环 542 bp 区域的核线粒体 DNA (NUMT) 相邻。从异质性负荷中排除 542 bp 内的异质性后，该区域不再显着。发现血液 mtDNA 异质性既是遗传的又是体细胞起源的，并且异质性负担的增加与血液中 mtDNA 拷贝数平均数量的减少密切相关，这些发现是 mtDNA 与疾病特征的关联研究中需要考虑的重要发现。