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

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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.