X-linked dystonia-parkinsonism (XDP, DYT3) is inherited in an X-linked recessive fashion and, due to a founder mutation, currently exclusively found in the Filipino population. Despite the highly penetrant nature of the causative genetic change, the clinical presentation of XDP, characterized by the coexistence of two overlapping phenotypes (dystonia and parkinsonism), shows extraordinary variability in the severity of signs as well as in age and site of disease onset. Interestingly, owing to the fact that all of the patients carry exactly the same disease-causing change and that most live in a similar environment on a genetically and geographically isolated island, individuals affected with XDP can be said to belong to one extended family, thereby representing a unique model system for studying genetic modifiers of disease penetrance and expression. The goal of Project P5 is to identify genetic factors in this model disease that modify the age and symptoms at onset, initial region affected by dystonia, initial parkinsonian symptom, and the time until dystonia generalizes. Within the framework of a collaboration between German and Filipino clinician-scientists, the applicants assembled/will collect DNA samples from ~800 carefully phenotyped patients with a confirmed molecular diagnosis of XDP. These samples will be included in a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) that together or independently influence disease expression in XDP (Objective 1). Additionally, the data generated by this microarray-based approach will be subjected to copy number variants (CNV) detection analyses. As natural extension of the first objective, we will perform in-depth and multipronged in-silico and in-vitro functional follow-up analyses of the most compelling results (Objective 2). Lastly, we will perform integrative and pathway analyses of results generated from these experiments, and compile these with data from an independent differential expression (RNA-Seq) study (Objective 3). Through the application and combination of a number of well-defined systematic experimental approaches, we will identify novel modifiers of penetrance and expressivity in XDP. While this project primarily targets a specific movement disorder occurring in a specific population, the insights gained from this work can be expected to also be relevant in other forms of dystonia and parkinsonism and, thus, feed directly into the analyses of other ProtectMove projects. P5 is headed by PIs that are well versed in molecular genetics and computational genomics.