Assessing mitochondrial variation associated with Alzheimer's Disease

National Institute On Aging

Investigators

Abstract

Genetic factors contribute substantially to the risk of Alzheimer's 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 17,000 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 subsequent analyses, we will utilize an additional ADSP case-control data set of 10,000 whole-exome sequenced individuals as an independent cohort to verify any identified AD association signals. In parallel, we will develop a computational pipeline for a mitochondrial genome-wide association study (mitoGWAS) specifically designed to identify mtDNA variants linked to diseases or traits. Knowledge of the specific mitochondrial involvement can help to understand the etiology of AD and could also lead to preventive interventions for Alzheimer's 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.