The ultimate goal of our research is to reduce the incidence of Parkinson?s disease (PD) by eliminating causal factors or delaying the age at onset. PD is a progressive movement disorder that affects 1-2% of the population over the age of 60, and many who are younger. Millions of individuals suffer from PD world-wide. Symptomatic treatment is available, but progression of disease and complications of therapy cause increasing disability. Effective intervention to reduce the incidence and delay the onset will require understanding the causes of PD and factors that modulate its expression. Both genes and environment are thought to play important roles in the pathogenesis of PD. The aims of this study are to identify genes that affect PD susceptibility and age at onset, and to study the interaction of these genes with two environmental factors that are inversely associated with PD risk; namely, smoking and coffee. Identifying susceptibility genes will provide clues to the causes of PD and may suggest new strategies for prevention. Genetic screening may be developed to identify at risk individuals for early intervention. Identifying genes that modulate age at onset will provide the necessary insight for developing ways to delay onset of symptoms. Studying the genetics of PD in the context of environmental factors will boost the power of the study and may help gain additional clues to disease pathogenesis. To achieve these aims we will perform a genome-wide association study with 2000 PD patients and 2000 control subjects, using genotyping technologies that allow analysis of single nucleotide polymorphisms and copy number variants. We will test each marker for main effect, gene x gene and gene x environment interactions, affecting risk or age at onset. The most promising findings will be replicated in independent data sets. Finally, since PD associated markers may only be proxies; fine mapping will be performed to pinpoint the actual PD genes. The infrastructure for this study is in place, including over 2000 well-characterized PD patients and 2000 controls, high quality DNA banked on all subjects, data on environmental exposures, and a multi-institutional interdisciplinary team of investigators with expertise in neurology, molecular genetics, statistical genetics, epidemiology, molecular biology and neuropathology. During the proposed study, we will continue to maintain this infrastructure, which was founded and supported by this grant since 1998.