Background Mitochondrial dysfunction manifests in neurodegenerative diseases and other age-associated disorders. In this study, we examined variation in inherited mitochondrial DNA (mtDNA) sequences in Black and White participants from 2 large aging studies to identify variants related to cognitive function. Methods Participants included self-reported Black and White adults aged ≥70 years in the Lifestyle Interventions and Independence for Elders (LIFE; N = 1 319) and Health Aging and Body Composition (Health ABC; N = 788) studies. Cognitive function was measured by the Digit-Symbol Substitution Test (DSST), and the Modified Mini-Mental State Examination (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined the joint effects of multiple variants across 16 functional mitochondrial regions with cognitive function using a sequence kernel association test. Based on these results, we prioritized meta-analysis of common variants in Black and White participants using mixed effects models. A Bonferroni-adjusted p value of <.05 was considered statistically significant. Results Joint variation in subunits ND1, ND2, and ND5 of Complex I, 12S RNA, and hypervariable region (HVR) were significantly associated with DSST and 3MSE at baseline. In meta-analyses among Black participants, variant m.4216T>C, ND1 was associated with a faster decline in 3MSE, and variant m.462C>T in the HVR was associated with a slower decline in DSST. Variant m.5460G>C, ND2 was associated with slower and m.182C>T in the HVR was associated with faster decline in 3MSE in White participants. Conclusions Among Black and White adults, oxidative phosphorylation Complex I variants were associated with cognitive function.

中文翻译：

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黑人和白人老年人的关节和个体线粒体 DNA 变异和认知结果


背景 线粒体功能障碍表现为神经退行性疾病和其他与年龄相关的疾病。在这项研究中，我们检查了 2 项大型衰老研究的黑人和白人参与者遗传线粒体 DNA （mtDNA） 序列的变异，以确定与认知功能相关的变异。方法 参与者包括自我报告的 ≥ 70 岁的黑人和白人成年人，参与老年人生活方式干预和独立性 （LIFE;N = 1 319）和健康衰老和身体成分 （Health ABC;N = 788） 研究。在 LIFE （3.6 年） 和 Health ABC （10 年） 的基线和随访期间，通过数字符号替代测试 （DSST） 和改良简易精神状态检查 （3MSE） 测量认知功能。我们使用序列核关联测试检查了 16 个功能线粒体区域与认知功能的多个变体的联合效应。基于这些结果，我们使用混合效应模型优先对黑人和白人参与者的常见变异进行荟萃分析。Bonferroni 调整后的 p 值为 <.05 被认为具有统计学意义。结果 复合物 I 、 12S RNA 和高变区 （HVR） 亚基 ND1 、 ND2 和 ND5 的关节变异与基线时 DSST 和 3MSE 显著相关。在黑人参与者的荟萃分析中，变异 m.4216T>C、ND1 与 3MSE 下降较快相关，HVR 变异 m.462C>T 与 DSST 下降较慢相关。在白人参与者中，变异 m.5460G>C、ND2 与较慢相关，HVR 中的 m.182C>T 与 3MSE 下降较快相关。结论 在黑人和白人成人中，氧化磷酸化复合物 I 变异与认知功能相关。