The main scientific theme of this project is to determine if the genetic epidemiology of Parkinson's disease (PD) is consistent with an etiologic role for inherited abnormalities of mitochondrial DNA (mtDNA). The presence of a mitochondrial complex I defect in subjects with PD is now well established. Furthermore, this defect appears to arise as a consequence of abnormalities in mtDNA. Whether these abnormalities of mtDNA are acquired or inherited is not known, but we have recently shown in a multi-generational family with PD in which transmission has been exclusively along maternal lines that maternal offspring have lower Complex I activity than paternal offspring. In Project 3 we will use data on family history of PD in PD subjects and controls generated by the Subject Accrual and Ascertainment component of the Core. These data will be examined to test three hypotheses regarding the role of mtDNA mutations in particular, and genetic risk factors in general, in the etiology of PD. Hypothesis 1: There is a predominance of maternal inheritance in PD. If inherited mtDNA mutations play a role in PD etiology, one would predict an excess of maternal inheritance. We will compare directly the number of affected mothers and fathers of probands using survival analysis. Logistic regression will be used to evaluate the influence of the gender of affected parents when probands have both an affected sibling and an affected parent, and to determine the relative risk of developing PD between PD subjects and controls when there is an affected mother versus an affected father. Hypothesis 2: Parkinson's disease susceptibility is determined by a major gene. We will perform a complex segregation analysis of a series of consecutively ascertained nuclear genetic families. Hypothesis 3: Certain disease characteristics of PD may be associated with familial or non-familial PD. Using logistic regression and analysis of variance, we will address the question of whether early age of onset, gender, or rapid symptom progression in PD is associated with a positive family history.