Assessing mitochondrial variation associated with Alzheimers Disease

遗传因素对阿尔茨海默病（AD）的风险有很大的影响。大规模的遗传关联研究已经确定了30多个迟发性阿尔茨海默病的易感位点，但阿尔茨海默病的大部分遗传能力仍未得到解释。一些研究人员提出线粒体变异与此有关，我们建议对这一假设进行关键测试，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，对来自3000例阿尔茨海默病病例和对照的全基因组序列数据进行分析，由阿尔茨海默病测序项目（ADSP）提供，以推断mtDNA变异和估计mtDNA拷贝数。然后，我们将测试mtDNA拷贝数或特定变体（本身或与核DNA变体结合）是否与AD风险相关。在进一步的分析中，我们将使用另一个由10,000个全外显子组测序个体组成的ADSP病例对照数据集作为独立队列，以测试任何已识别的AD关联信号的复制。了解特定的线粒体参与可以帮助了解阿尔茨海默病的病因，也可能导致对阿尔茨海默病的预防性干预——可以想象的是其他形式的痴呆症。此外，该项目开发的计算程序可以进一步应用于研究公共领域数十万个全基因组和全外显子组测序基因组的mtDNA动力学；在这些队列中进行与阿尔茨海默病或其他感兴趣的疾病相关的可比较的前瞻性试验可能最终是一个进一步的目标。

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.