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

摘要 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里 细胞质，并提供我们维持生命所需的几乎所有能量。因此，理所当然地认为 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。这个 然而，菲尔德还没有广泛地检验这一假设，很大程度上是因为生物特征或 我们用来估计核DNA效应的家庭模型与对 线粒体DNA由于其独特的特征和遗传模式(例如，线粒体DNA自我复制 无性繁殖，并直接沿着母系传播)。目前的R01寻求开发， 验证并测试一个模型，该模型利用mtDNA遗传的这种单一模式来估计 线粒体DNA变异所占的变异比例(MT2)。我们怀疑表亲们会是一个 在这方面，一组亲属的信息尤其丰富。包括远亲在内的母系表亲， 几乎分享了他们所有的线粒体DNA。相比之下，父系表亲通常并不共享mtDNA。我们 将利用母系和父系的这种差异来估计MT2。一旦开发和使用 经过验证，我们将在多代家系中约480万人的样本中运行该模型 4到17代人，与每年更新的医疗和生命记录有关， 在过去的25年里出现了。分析将集中在阿尔茨海默病(AD)和其他关键疾病 老龄化后果(糖尿病、自杀、帕金森氏症和长寿)。这样，拟议的 R01不仅应该对阿尔茨海默病的起源和相关的衰老状况产生关键的新见解， 但也将开发新的方法来建立亟需的贝叶斯“先例”，以指导未来 线粒体DNA作用的研究。

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.