线粒体 DNA 拷贝数与脑 MRI 标志物和认知功能的关联：基于社区队列的荟萃分析。
Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.
机构信息
From the Department of Biostatistics (Y.Z., X.L., A.P., A.S.B., C.L.), School of Public Health, Boston University, MA; Cardiovascular Health Research Unit (K.L.W., J.C.B.), Department of Medicine, University of Washington, Seattle; Brigham and Women's Hospital (N.K., T.S.), Boston, MA; The Institute for Translational Genomics and Population Sciences (X.G., J.I.R.), Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance; Department of Psychiatry and Behavioral Sciences (A.L.R., D.C.G.), Boston Children's Hospital, MA; Department of Psychiatry (A.L.R., D.C.G.), Harvard Medical School, Boston Children's Hospital, MA; Department of Epidemiology (W.Z., S.M.R., S.L.R.K., J.A.S.), School of Public Health, University of Michigan, Ann Arbor; GeneSTAR Research Program (L.R.Y.), Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; School of Medicine (J.S.A.P.), Universidad de Los Andes, Bogotá, Colombia; Harvard Medical School (T.S.), Boston, MA; McKusick-Nathans Institute (D.E.A.), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology (T.R.A.), University of Washington, Seattle; Department of Neurology (A.S.B.), School of Medicine, Boston University, MA; Framingham Heart Study (A.S.B., D.L., S.S., V.R., C.L., C.L.S.), Framingham, MA; Department of Human Genetics and South Texas Diabetes and Obesity Institute (J. Blangero, J.E.C.), University of Texas Rio Grande, Brownsville; Human Genetics Center (E.B., J. Bressler), School of Public Health, The University of Texas Health Science Center at Houston; Human Genome Sequencing Center (E.B.), Baylor College of Medicine, Houston, TX; Department of Preventive Medicine (L.H.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Internal Medicine (T.M.H.), Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC; National Institute on Aging (L.J.L.), and Population Sciences Branch National Heart, Lung, and Blood Institute (D.L.), NIH, Bethesda, MD; Memory Impairment and Neurodegenerative Dementia (MIND) Center (T.H.M.), School of Medicine, University of Mississippi Medical Center, Jackson; Center for Biomedical Image Computing and Analytics (I.M.N.), Department of Radiology, University of Pennsylvania, Philadelphia; Center for Public Health Genomics (S.S.R.), University of Virginia School of Medicine, Charlottesville; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S., C.L.S.), University of Texas Health Science Center at San Antonio; Institute of Gerontology & Department of Healthcare Sciences (W.T.), Wayne State University, Detroit, MI; Department of Neurosciences (K.A.G.) and Shiley-Marcos Alzheimer's Disease Center (H.M.G.), University of California, San Diego, La Jolla; Department of Medicine (V.R.), School of Medicine, and Department of Epidemiology, Boston University, MA; University of California, San Francisco (K.Y.); Department of Neurology (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle; Department of Neurology (C.S.D.), UC Davis, CA; Institute of Molecular Medicine (M.F.), McGovern Medical School; and Human Genetics Center (M.F.), School of Public Health, University of Texas Health Science Center at Houston; and Cardiovascular Health Research Unit and Department of Epidemiology (S.R.H.), and Departments of Family Medicine, Epidemiology, and Global Health (A.L.F.), University of Washington, Seattle.
出版信息
Neurology. 2023 May 2;100(18):e1930-e1943. doi: 10.1212/WNL.0000000000207157. Epub 2023 Mar 16.
BACKGROUND AND OBJECTIVES
Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.
METHODS
We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality.
RESULTS
We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.
DISCUSSION
Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.
背景和目的
先前的研究表明，线粒体 DNA（mtDNA）拷贝数（CN）较低与神经退行性疾病有关。然而，全血中的 mtDNA CN 是否与阿尔茨海默病（AD）的内表型和 AD 相关痴呆（AD/ADRD）有关，仍需进一步研究。我们评估了 mtDNA CN 与认知功能和社区中年至老年人的 MRI 测量值之间的关联。
方法
我们纳入了来自 9 个不同社区的、具有全基因组测序的、无痴呆症的 TOPMed 计划参与者。循环 mtDNA CN 被估计为 mtDNA 平均覆盖率与核 DNA 平均覆盖率的两倍。脑 MRI 标志物包括总脑、海马体和脑白质高信号体积。一般认知功能来自不同的认知领域。我们对 AD/ADRD 内表型进行了队列特异性关联分析，这些内表型评估的时间在采血后±5 年内（即横断面分析）或 5-20 年内（即前瞻性分析），并对潜在混杂因素进行了调整。我们进一步按性别和年龄（<60 岁与≥60 岁）进行分层分析。采用固定效应或样本量加权的荟萃分析来合并结果。最后，我们进行了孟德尔随机化（MR）分析来评估因果关系。
结果
我们纳入了多达 19152 名参与者（平均年龄 59 岁，57%为女性）。较高的 mtDNA CN 与一般认知功能较好呈横断面相关（β=0.04；95%CI 0.02-0.06），与年龄、性别、批次效应、种族/民族、采血与认知评估之间的时间、队列特异性变量和教育无关。进一步调整血细胞计数或心血管代谢特征会导致结果略有减弱。我们在前瞻性分析中观察到与认知功能类似的显著关联，尽管关联幅度较小。我们在荟萃分析中没有发现 mtDNA CN 与脑 MRI 测量值之间的显著关联。MR 分析并未显示血液中 mtDNA CN 与认知之间存在因果关系。
讨论
在美国各地的大型和多样化社区中，较高的血液 mtDNA CN 与当前和未来的一般认知功能较好有关。尽管 MR 分析不支持因果关系，但需要进一步研究来评估因果关系。循环 mtDNA CN 可以作为社区中当前和未来认知功能的生物标志物。
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