This is a competing continuation application for the grant ES10751 entitled "Molecular Epidemiology of Parkinson's Disease". Key steps in the pathogenesis of Parkinson's disease (PD) may include increased soluble alpha-synuclein and its aggregation and fibrillization. These events are attenuated by protein degradation and fibril sequestration. The linkage-derived genes alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), microtubule-associated protein tau (MAPT), and parkin (PRKN) confer PD susceptibility, possibly via their effects on this pathogenesis pathway. We postulate that functional variability in these four genes and their joint effects modify PD severity outcomes, and that age, gender, and environmental factors also contribute to susceptibility and outcomes. We propose renewal of our grant ES10751 with the following 3 specific aims: A1. To refine the association between linkage-derived susceptibility genes and PD. Human, primate, and rodent cross-species sequence conservation will be used to highlight functional domains within the SNCA, UCHL1, MAPT, and PRKN loci. Additional variants, including single nucleotide polymorphisms (SNPs), will be identified within these regions (VISTA or "vSNPs"). Linkage disequilibrium will be used to identify haplotype-tagging variants ("ht-SNPs"). Family-based and case-control association analyses will be performed in an expanded Mayo sample of 1,500 matched pairs of PD cases and unaffected siblings or unrelated population controls. A2. To study interactions of these genes, and their interactions with environmental and gender-related factors. Using data from aim 1, we will apply recursive partitioning and conditional logistic regression approaches to investigate the joint effects of SNCA, UCHL1, MAPT, and PRKN on PD. We will also determine how these genes interact with environmental risk factors including pesticides, tobacco, coffee, and alcohol. In addition, we will assess how gender and endogenous or exogenous estrogen modify these interactions in women. A3. To study genetic factors influencing PD outcomes. In an established cohort of 1,000 Mayo PD patients, we will perform longitudinal assessments and conduct survival and regression analyses to determine whether polymorphism in the SNCA, UCHL1, MAPT, and PRKN genes correlates with disease severity outcomes. In particular, we will consider death, nursing home placement, incident dementia, and Hoehn and Yahr stage. We will also consider activities of daily living, complications of therapy, and quality of life. The first two aims will refine our understanding of molecular targets for neuroprotective therapies, and the third aim will predict their efficacy. Our findings will contribute to early disease detection (biomarkers) and primary prevention strategies. They will also accelerate the development of new treatments, reduce research and development costs, and identify subgroups of patients most likely to benefit.