Reduced penetrance of Parkinson s disease (PD) can present itself as lifetime absence of disease in carriers of pathogenic mutations. This phenomenon has been described for carriers of causative PD mutations in the genes LRRK2, GBA, Parkin, PINK1, and VPS35. Furthermore, a delay in age at onset (AAO) represents another example of reduced penetrance in age-dependent diseases such as PD. In both cases, the underlying heritable or environmental/lifestyle modifiers leading to reduced penetrance remain largely elusive, which can at least in part be attributed to the scarcity of carefully recruited and thoroughly phenotyped cohorts with available DNA samples. The overarching aim of Project P7 is thus to identify and further characterize modifiers of penetrance in PD using the carefully characterized, mainly population-based, multi-centric cohorts available to the ProtectMove Consortium. Specifically, we will search for genetic and environmental/lifestyle factors in PD that reduce the penetrance of disease-causing mutations or delay AAO. First, we will identify carriers of known disease-causing mutations by screening approximately 21,400 individuals from the ProtectMove PD case-control cohorts, using the NeuroChip or ExomeChip content (Objective 1). Unaffected carriers will be systematically compared to affected mutation carriers, focusing on genetic modifiers based on data derived from genome-wide microarrays and environmental/lifestyle exposures as well as on interactions between genetic and environmental/lifestyle factors with regard to PD status (Objective 2). In another set of analyses, genetic and environmental/lifestyle modifiers of AAO will be investigated in approximately 6,000 PD cases (Objective 3). We will further assess the impact of discovered penetrance-modifying genetic variants on clinical and pre-clinical disease characteristics in ProtectMove cohorts, while also validating our results in independent datasets (Objective 4). Finally, we will investigate the overlap of genetic determinants of AAO by performing cross-phenotype analyses between PD, dystonia (DYT), and X-linked dystonia-parkinsonism (XDP) (Objective 5). Heading this project are two PIs with extensive experience and a good publishing record in biostatistics and genetic epidemiology. The project is an integral part of ProtectMove as all available ProtectMove cohorts will be used to generate data, and analyses will be integrated with results obtained from other research unit projects. Furthermore, follow-up fine-mapping and functional characterization to be performed during years 4-6 will take advantage of collaborations established through the Research Unit.