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

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.

Grant Number: 4R01AG073189-02
NIH Institute/Center: NIH
Principal Investigator: S. Alexandra Burt