Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of the disease. The etiology of PD is not well understood. Most of the PD cases are sporadic. However, approximately 5-10% of PD patients may have a clear familial history, exhibiting a classical recessive or dominant Mendelian mode of inheritance. Genetic studies in the past more than 10 years have played a vital role in understanding the etiology and pathogenic mechanism of PD. But, the power of genetic study is greatly limited because it requires sufficient number of informative meiosis, i.e. large families with both normal and affected members, especially when great genetic heterogeneity exists. It is particularly a difficult task for most of the late onset neurodegenerative disorders, including PD. Because PD is a late-onset disease with an average age of onset between 60 and 80 years, it is practically rather difficult to collect large PD families and DNA samples. Collection of a large PD family with 2-3 generations normally takes decades. Thus, collection of the large kindreds with PD represents a significant hurdle for identification of new PD-causing genes. Through a 19-year collaborative effort initiated from 1992, we and our collaborators have identified a large PD family with 67 members, among whom 11 members are affected. We have collected clinical information and DNA samples from 62 members, including DNA samples from 10 affected individuals. During this period, two affected and one unaffected members died and were autopsied. Pathological analysis of the two autopsy samples revealed Parkinson pathology, including typical Lewy bodies. But the unaffected member did not show PD pathology. These data suggest that the PD in this kindred is similar to idiopathic PD. Supported by the American Parkinson Disease Association (APDA);we excluded mutations in currently known PD-causing genes, indicating a novel PD locus. We then carried out a genome-wide linkage analysis. The known PD-loci were excluded and a candidate PD-linked locus was suggested on the short arm of chromosome 20. This project is designed to identify a novel PD-causing gene by combined use of the recently developed exome sequencing approach and the unique resources that we have accumulated in the past 19 years. The candidate gene identified in this PD family will be further tested in over 500 familial PD probands. This gene may represent the third gene with a high penetrance for autosomal dominant PD. Completion of this project may not only lead to identification of the genetic basis of PD in this kindred, but also provides the PD research community with a novel molecular target for further studies of the disease mechanisms, biological pathways and potential therapeutic strategies. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of the disease. The etiology of PD is not well understood. Genetic studies in the past more than 10 years have played a vital role in understanding the etiology and pathogenic mechanism of PD. Through a 19-year collaborative effort, we have identified a large PD family and collected DNA samples. Genetic sequencing and mapping studies indicate a new locus for autosomal dominant form of PD. In this application, we propose to identify a novel PD-causing gene using these unique genetic materials and recently developed whole exome sequencing technology. Completion of this project may lead to the discovery of a novel molecular target for further studies of the disease mechanisms, biological pathways and potential therapeutic strategies.