Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic Traits

线粒体 DNA 拷贝数和序列变异与年龄、阿尔茨海默病相关表型和年龄相关代谢特征的关系

• 批准号: 9980748
• 负责人: Chunyu Liu
• 金额: $ 63.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980748
• 关键词: Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; American; Birth; Blood; Blood Glucose; Blood Pressure; Brain; Cardiomyopathies; Cell physiology; Cells; Cerebrospinal Fluid; Chronic Disease; Clinic; Cognitive; Complex; DNA copy number; Data; Dementia; Diabetes Mellitus; Disease; Early Diagnosis; Early treatment; Elderly; Ethnic group; European; Fasting; Fertility; Gender; Genetic Polymorphism; Genome; Goals; Hair; Health Care Costs; Hereditary Disease; Hippocampus (Brain); Human; Hyperlipidemia; Hypertension; Inherited; Investigation; Knowledge; Late Onset Alzheimer Disease; Link; Lipids; Longevity; Magnetic Resonance Imaging; Measures; Metabolic; Metabolic Diseases; Methods; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Mothers; Mus; Mutation; National Heart, Lung, and Blood Institute; Obesity; Outcome; Phenotype; Premature aging syndrome; Prevention; Prospective cohort; Public Health; Research; Risk Factors; Role; Sampling; Somatic Mutation; Speed; Spinal; Statistical Methods; Structure; Symptoms; Testing; Time; Trans-Omics for Precision Medicine; Variant; White Matter Hyperintensity; Work; age related; aging brain; base; cardiometabolism; cognitive function; cohort; cost; follow-up; frailty; genome sequencing; hearing impairment; human data; human disease; impaired brain development; insight; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; mortality; mouse model; novel; novel strategies; prevent; trait; whole genome

Abstract Aging is the main risk factor for many chronic diseases, including late onset Alzheimer's disease (LOAD) and many age-related metabolic diseases, such as obesity and diabetes. Using AD as an example, the number of people with AD doubles every 5 years beyond age 65. In 2017, 5.3 million Americans 65 years or older are affected by LOAD. The burden of health care costs for LOAD is enormous – $259 billion in 2017. Thus, early detection and treatment of these age-related diseases should be a core tenet of public health. Research is needed to guide such efforts. Over the last decade, accumulating evidence has linked aging to mitochondrial dysfunction. Mitochondria are tiny powerhouses, generating more than 90% of energy to support normal cellular function. Mitochondria contain their own genome (mtDNA) which is both polymorphic and heteroplasmic, i.e., two or more mtDNA alleles can co-exist in the same cell due to the presence of many mtDNA molecules within any cell. Previous studies in Europeans have found that reduced mtDNA copy number was associated with frailty and higher mortality among elderly. Furthermore, reduced mtDNA copy number in human cerebrospinal fluid was observed at least a decade before clinic AD symptoms develop. These findings in Europeans need to be generalized in other ethnic groups. Several hundreds of mtDNA rare mutations have been described to cause mostly rare, yet severe maternally inherited diseases. A limited number of common mtDNA polymorphisms were examined in relation to metabolic disorders, dementia and cognitive functions. Robust associations, however, haven't been established between common mtDNA polymorphisms and age-related common diseases. In most of these previous studies, heteroplasmic mtDNA mutations haven't been well studied with respect to aging and age-related human diseases because, until recently, sequencing has been extremely costly. Studying a spectrum of mtDNA mutations along with mtDNA copy number in relation to age-related traits in large samples has now become possible thanks to drastically decreased whole genome sequencing costs. This proposed study will leverage five prospective cohorts, each with whole genome sequencing data generated from the National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) and extensive cognitive, brain structure, and cardiometabolic measures. The expected outcomes of the work proposed are to 1) develop a novel statistical method to identify age-related heteroplasmic (i.e., somatic) mtDNA mutations, and 2) develop a statistical framework to analyze mtDNA copy number and heteroplasmic mutations in relation to key age-related disorders, include LOAD and age-related metabolic traits. Results of this investigation are expected to advance understanding of the role of aging on the mitochondrial genome, and in turn, the contributions of mitochondrial genome to age-related traits. Equally important, a positive impact of this project will be advancing knowledge of the role of mtDNA in a spectrum of age-related complex phenotypes.

摘要 衰老是许多慢性疾病的主要危险因素，包括迟发性阿尔茨海默病（LOAD）和 许多与年龄有关的代谢疾病，如肥胖和糖尿病。以AD为例， 65岁以上的AD患者每5年翻一番。2017年，530万65岁或以上的美国人 受负载影响。LOAD的医疗保健费用负担是巨大的-2017年为2590亿美元。因此，早期 检测和治疗这些与年龄有关的疾病应成为公共卫生的核心原则。研究是 需要指导这些努力。 在过去的十年中，越来越多的证据将衰老与线粒体功能障碍联系起来。线粒体是 微型发电站，产生超过90%的能量来支持正常的细胞功能。线粒体含有 他们自己的基因组（mtDNA），既多态又异质，即，两个或多个mtDNA等位基因可 由于任何细胞内都存在许多mtDNA分子，因此它们在同一细胞中共存。既往研究 欧洲人发现，线粒体DNA拷贝数减少与老年人的虚弱和较高的死亡率有关。 老人此外，至少在十年前就观察到人类脑脊液中mtDNA拷贝数减少 在临床AD症状出现之前。欧洲人的这些发现需要推广到其他种族群体。 据报道，数百种线粒体DNA罕见突变可导致大多数罕见但严重的母系遗传。 遗传性疾病。有限数量的常见mtDNA多态性与代谢相关性进行了研究。 疾病、痴呆和认知功能。然而，还没有建立强有力的联系， 常见mtDNA多态性和与年龄相关的常见疾病。在以前的大多数研究中， 异质性mtDNA突变与衰老和年龄相关人类的关系尚未得到充分研究， 疾病，因为直到最近，测序的成本仍然极其昂贵。研究线粒体DNA的光谱 突变沿着mtDNA拷贝数与大样本中年龄相关性状的关系现已成为 这要归功于全基因组测序成本的大幅降低。 这项拟议的研究将利用五个前瞻性队列，每个队列都生成了全基因组测序数据 来自国家心脏，肺和血液研究所（NHLBI）的Trans-Omics for Precision Medicine（TOPMed）和 广泛的认知、大脑结构和心脏代谢指标。工作的预期成果 提出了1）开发一种新的统计方法来鉴定年龄相关的异质性（即，线粒体DNA 突变，以及2）开发一个统计框架来分析mtDNA拷贝数和异质性突变 与关键的年龄相关疾病相关，包括负载和年龄相关的代谢特征。成果 研究有望促进对线粒体基因组衰老作用的理解， 反过来，线粒体基因组对年龄相关性状的贡献。同样重要的是， 该项目将进一步了解mtDNA在一系列与年龄相关的复杂表型中的作用。