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

基本信息

批准号：
10212947
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-05-31
项目状态：
已结题

项目摘要

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.

抽象的衰老是许多慢性疾病的主要危险因素，包括晚发性阿尔茨海默病 (LOAD) 和许多与年龄相关的代谢疾病，例如肥胖和糖尿病，以 AD 为例。 65 岁以上，患有 AD 的人数每 5 年增加一倍。2017 年，65 岁或以上的美国人有 530 万受 LOAD 影响，LOAD 的医疗保健费用负担巨大——2017 年为 2590 亿美元。因此，早期检测和治疗这些与年龄相关的疾病应该是公共卫生研究的核心原则。需要指导此类努力。在过去的十年中，越来越多的证据表明衰老与线粒体功能障碍有关。微小的发电站，产生超过 90% 的能量来支持线粒体的正常细胞功能。他们自己的基因组（mtDNA）既是多态性又是异质性的，即两个或多个mtDNA等位基因可以由于任何细胞内都存在许多 mtDNA 分子，因此它们共存于同一细胞中。欧洲人发现，线粒体 DNA 拷贝数减少与体质虚弱和死亡率较高有关。此外，至少十年来观察到人类脑脊液中线粒体DNA拷贝数减少。在出现临床 AD 症状之前，欧洲人的这些发现需要推广到其他种族群体。据描述，数百种 mtDNA 罕见突变可导致大多数罕见但严重的孕产妇疾病。研究人员对有限数量的常见 mtDNA 多态性与代谢的关系进行了检查。然而，疾病、痴呆和认知功能之间尚未建立牢固的关联。常见的 mtDNA 多态性和与年龄相关的常见疾病在大多数先前的研究中，异质性 mtDNA 突变尚未在衰老和与年龄相关的人类方面得到充分研究因为直到最近，研究 mtDNA 谱系的成本仍然极其高昂。大样本中与年龄相关性状相关的突变以及 mtDNA 拷贝数现已成为这得益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，每个队列都会生成全基因组测序数据来自国家心肺血液研究所 (NHLBI) 精准医学跨组学 (TOPMed) 和广泛的认知、大脑结构和心脏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，2) 开发统计框架来分析 mtDNA 拷贝数和异质突变与关键的年龄相关疾病相关，包括负荷和年龄相关的代谢特征。研究预计将促进对衰老对线粒体基因组的作用的理解，并在反过来，线粒体基因组对年龄相关性状的贡献也同样重要，它产生了积极的影响。该项目将增进对线粒体 DNA 在一系列与年龄相关的复杂表型中的作用的了解。