A novel family-based model to evaluate the role of mitochondrial DNA in neuropsychiatric phenotypes

Mitochondrial DNA is distinct from nuclear DNA in two key ways: it is passed exclusively through the maternal line, and is passed essential intact from mothers to their children (i.e., it recombines with copies of itself). As... [ view full abstract ]

Mitochondrial DNA is distinct from nuclear DNA in two key ways: it is passed exclusively through the maternal line, and is passed essential intact from mothers to their children (i.e., it recombines with copies of itself). As such, all offspring that are biologically related through their mothers have identical mitochondrial DNA.  This includes all full siblings, maternal half-siblings, and cousins who are related through their mothers, but not paternal half-siblings or cousins who are related through their fathers.  We argue that this unique inheritance pattern can be exploited to quantify the effects of mitochondrial DNA on phenotypes.  Such work would be critically important, not only for clarifying the presence or absence of mtDNA effects, but also because it would establish a clear prior for subsequent molecular genetic studies (as twin studies did for nuclear DNA).  We will evaluate the utility of our new family-based model several ways: first, we will conduct a series of simulation studies in a variety of family structures to ensure that our model identifies the effects as intended.  Second, we will run a series of power analyses, again in a variety of family structures, to get a sense of the samples sizes necessary to detect mtDNA.  Third, we will run the model in two children-of-twin samples, each with roughly 1000 twin pairs and their children.  We also hope to run the model in a large population-based registry (active discussions are underway). Implications from our results, and complications to be considered in the future, will be discussed.