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

摘要 老龄化是许多慢性病的主要风险因素，包括晚发性阿尔茨海默病(LOAD)和 许多与年龄相关的代谢性疾病，如肥胖和糖尿病。以AD为例， 65岁以上的阿尔茨海默病患者每5年增加一倍。2017年，530万65岁或以上的美国人 受负荷影响。医疗保健成本的负担是巨大的-2017年为2590亿美元。因此，早些时候 发现和治疗这些与年龄有关的疾病应该是公共卫生的核心原则。研究是 指导这类努力所需的资源。 在过去的十年里，越来越多的证据将衰老与线粒体功能障碍联系在一起。线粒体是 微小的发电站，产生90%以上的能量来支持正常的细胞功能。线粒体包含 他们自己的基因组(MtDNA)既是多态的，也是异质的，即两个或更多的mtDNA等位基因可以 由于在任何细胞内都存在许多线粒体DNA分子，所以在同一细胞中共存。之前的研究在 欧洲人发现，线粒体DNA拷贝数减少与虚弱和更高的死亡率有关 老年人。此外，人类脑脊液中mtdna拷贝数的减少至少观察到了十年。 在临床出现阿尔茨海默病症状之前。在欧洲人中的这些发现需要在其他民族中推广。 数百种罕见的线粒体DNA突变已被描述为大多数罕见但严重的母体突变。 遗传性疾病。少数常见的线粒体DNA多态与代谢有关。 障碍、痴呆症和认知功能。然而，两者之间还没有建立起牢固的联系 常见线粒体DNA多态与年龄相关常见病。在之前的大多数研究中， 关于衰老和与年龄相关的人类的线粒体DNA异质性突变还没有得到很好的研究 疾病，因为直到最近，测序一直是极其昂贵的。线粒体DNA谱的研究 大样本中与年龄相关性状的突变以及线粒体DNA拷贝数现在已经成为 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，每个队列都产生了全基因组测序数据 来自国家心、肺和血液研究所(NHLBI)的精密医学全基因组学(TOPMed)和 广泛的认知、大脑结构和心脏新陈代谢测量。工作的预期结果 建议1)开发一种新的统计方法来识别与年龄相关的异质性(即体细胞)mtDNA 突变，以及2)建立一个统计框架来分析线粒体DNA拷贝数和异质突变 在与年龄相关的关键疾病方面，包括负荷和与年龄相关的代谢特征。这样做的结果是 研究有望促进对衰老在线粒体基因组上的作用的理解，以及在 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，这会产生积极的影响 该项目将促进对线粒体DNA在一系列与年龄相关的复杂表型中的作用的了解。

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.