Quantifying the contributions of mitochondrial DNA to Alzheimer's Disease and related conditions of aging

量化线粒体 DNA 对阿尔茨海默病和相关衰老状况的影响

基本信息

批准号：
10269143
负责人：
S. Alexandra Burt
金额：
$ 154.29万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269143
关键词：
Aerobic Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Bacteria Biometry Birds Birth Certificates Characteristics Communities Cytoplasm DNA Data Set Death Certificates Development Diabetes Mellitus Disease Distant Elements Environment Etiology Extended Family Family Family member Fishes Food Foundations Functional disorder Future Generations Genetic Genetic Recombination Germ Cells Individual Inheritance Patterns Inherited Joints Knowledge Life Link Longevity Mammals Medical Medical Records Meiosis Methods Mitochondria Mitochondrial DNA Mitochondrial Inheritance Modeling Mothers Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Family Organelles Organism Outcome Parkinson Disease Pattern Population Population Database Probability Production Records Regulation Reproductive Process Research Role Running Sampling Sensitivity and Specificity Ships Statistical Models Suicide Symptoms Testing Time Uncertainty Update Utah Variant Walking Work asexual base genetic pedigree human disease insight interest intergenerational knowledge base mitochondrial dysfunction mitochondrial genome next generation novel offspring transmission process virtual

项目摘要

ABSTRACT Mitochondria are bacteria-like organelles with their own DNA (mtDNA). They reside in our cellular cytoplasm, and provide nearly all of the energy we use to sustain life. It thus stands to reason that inherited mtDNA dysfunction is an important element of diseases characterized by low energy. The field has yet to broadly examine this hypothesis, however, in large part because the biometric or family models we use to estimate the effects of nuclear DNA are totally incompatible with the study of mtDNA due to its unique characteristics and pattern of inheritance (e.g., mtDNA reproduces itself asexually and is transmitted directly down the maternal line). The current R01 seeks to develop, validate, and test a model that leverages this singular pattern of mtDNA inheritance to estimate the proportions of variance accounted for by variation in mtDNA (mt2). We suspect that cousins will be a particularly informative set of relatives in this regard. Matrilineal cousins, including very distant ones, share virtually all of their mtDNA. Patrilineal cousins, by contrast, do not typically share mtDNA. We will exploit this difference in the maternal and paternal lines to estimate mt2. Once developed and validated, we will run this model in a sample of ~4.8 million individuals in multigenerational pedigrees 4 to 17 generations deep, which have been linked to annually updated medical and vital records that have arisen over the last 25 years. Analyses will focus on Alzheimer's Disease (AD) and other key aging outcomes (diabetes, suicide, Parkinson's Disease, and longevity). In this way, the proposed R01 should not only yield critical new insights into the origins of AD and related conditions of aging, but will also develop novel methods to establish much needed Bayesian `priors' to guide future research in the role of mtDNA.

抽象的线粒体是类似细菌的细胞器，有自己的 DNA (mtDNA)。它们驻留在我们的细胞中细胞质，并提供我们维持生命所需的几乎所有能量。因此，按理说遗传性线粒体DNA功能障碍是以低能量为特征的疾病的重要因素。这然而，该领域尚未广泛检验这一假设，这在很大程度上是因为生物识别或我们用来估计核 DNA 影响的家庭模型与以下研究完全不相容： mtDNA由于其独特的特征和遗传模式（例如，mtDNA自我复制）无性繁殖并直接沿母系传播）。目前的R01力求发展，验证并测试一个模型，该模型利用 mtDNA 遗传的这种奇异模式来估计 mtDNA (mt2) 变异造成的变异比例。我们怀疑表兄弟姐妹会是在这方面特别有信息的亲戚。母系表兄弟姐妹，包括远房亲戚，他们几乎共享所有线粒体DNA。相比之下，父系表兄弟姐妹通常不共享线粒体DNA。我们将利用母系和父系的这种差异来估计 mt2。一旦开发并经过验证，我们将在多代谱系中约 480 万人的样本中运行该模型 4 至 17 代深度，与每年更新的医疗和重要记录相关联是在过去 25 年里出现的。分析将重点关注阿尔茨海默病 (AD) 和其他关键疾病衰老结果（糖尿病、自杀、帕金森病和长寿）。这样，提出的 R01 不仅应该对 AD 的起源和相关的衰老状况产生重要的新见解，但还将开发新颖的方法来建立急需的贝叶斯“先验”来指导未来线粒体DNA作用的研究。