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 two 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=1319) and Health Aging and Body Composition (Health ABC; N=7888) studies. Cognitive function was measured by the digit-symbol substitution test (DSST), and the Modified Mini-Mental State Exam (3MSE) at baseline and over follow-up in LIFE (3.6 years) and Health ABC (10 years). We examined 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 <0.05 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. Conclusion 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联合和个体线粒体 DNA 变异和认知结果


背景线粒体功能障碍表现在神经退行性疾病和其他与年龄相关的疾病中。在这项研究中，我们检查了两项大型衰老研究中黑人和白人参与者遗传线粒体 DNA (mtDNA) 序列的变异，以识别与认知功能相关的变异。方法 参与者包括生活方式干预和老年人独立 (LIFE; N=1319) 以及健康老龄化和身体成分 (Health ABC; N=7888) 研究中自我报告的年龄 ≥ 70 岁的黑人和白人成年人。认知功能通过数字符号替代测试（DSST）和改良简易精神状态检查（3MSE）在基线和 LIFE（3.6 年）和 Health ABC（10 年）随访中进行测量。我们使用序列核关联测试检查了 16 个功能性线粒体区域的多种变异与认知功能的联合效应。基于这些结果，我们优先使用混合效应模型对黑人和白人参与者的常见变异进行荟萃分析。 Bonferroni 调整 p 值为 <0.05 被认为具有统计显着性。结果 复合物 I、12S RNA 和高变区 (HVR) 亚基 ND1、ND2 和 ND5 的联合变异与基线时的 DSST 和 3MSE 显着相关。在黑人参与者的荟萃分析中，变异 m.4216T>C、ND1 与 3MSE 较快下降相关，而 HVR 中的变异 m.462C>T 与 DSST 较慢下降相关。在白人参与者中，HVR 中的变体 m.5460G>C、ND2 与较慢的 3MSE 下降相关，而 m.182C>T 与 3MSE 的较快下降相关。结论 在黑人和白人成年人中，氧化磷酸化复合物 I 变异与认知功能相关。