Assessing mitochondrial variation associated with Alzheimer's Disease

遗传因素对阿尔茨海默病（AD）的风险有很大影响。大规模的遗传关联研究已经确定了30多个迟发性AD的易感基因座，但AD的遗传性仍无法解释。一些研究人员提出线粒体变异参与其中，我们建议对这一假设进行关键性检验，评估线粒体DNA（mtDNA）拷贝数和/或变异的变化对风险的影响程度。我们的方法将应用我们开发的计算程序，从阿尔茨海默病测序项目（ADSP）提供的3,000例AD病例和对照组的全基因组序列数据中，推断mtDNA变异和mtDNA拷贝数的估计。然后，我们将测试mtDNA拷贝数或特定变异-无论是本身还是与核DNA变异相结合-是否与AD风险相关。在进一步的分析中，我们将使用另一个ADSP病例对照数据集，其中包含10，000名全外显子组测序的个体，作为一个独立的队列，以测试任何已识别的AD相关信号的复制。了解特定的线粒体参与可以帮助了解AD的病因，也可以导致阿尔茨海默病的预防干预-以及其他形式的痴呆症。此外，该项目中开发的计算程序可以进一步应用于研究公共领域中数十万个全基因组和全外显子组测序基因组中的mtDNA动态;这些队列中与AD或其他感兴趣疾病相关的可比前瞻性测试最终可能是进一步的目标。

Genetic factors contribute substantially to the risk of Alzheimers Disease (AD). Large-scale genetic association studies have identified more than 30 susceptibility loci for late-onset AD, but much of the genetic heritability of AD remains unexplained. Some researchers have proposed that mitochondrial variation is involved, and we propose to do a critical test of this hypothesis, assessing the extent to which changes in mitochondrial DNA (mtDNA) copy number and/or variants contribute to risk. Our approach will apply computational programs we have developed to whole-genome sequence data from 3,000 AD cases and controls, provided by the Alzheimer's Disease Sequencing Project (ADSP), to infer mtDNA variants and estimates of mtDNA copy number. We will then test whether mtDNA copy number or specific variants -- either themselves or in combination with nuclear DNA variants -- are associated with AD risk. In further analyses, we will use another ADSP case-control data set of 10,000 whole-exome sequenced individuals as an independent cohort to test for replication of any identified AD association signals. Knowledge of the specific mitochondrial involvement can help to understand the etiology of AD and could also lead to preventive interventions for Alzheimers Disease -- and conceivably other forms of dementia. In addition, the computational programs developed in the project could be further applied to study mtDNA dynamics in the hundreds of thousands of whole-genome and whole-exome sequenced genomes in the public domain; comparable prospective tests of associations with AD or other diseases of interest in those cohorts could eventually be a further goal.