Comprehensive Unbiased Risk factor Assessment for Genetics and Environment in Parkinson's Disease

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Despite the advances in the identification of genes involved in Parkinson's disease (PD), there are still appreciable gaps in our understanding of PD. Therefore we propose a comprehensive approach based on (i) a unique collection of families and (ii) large cohorts of sporadic PD patients for (iii) genetic studies and (iv) assessment of environmental modifiers that will translate into (v) functional validation studies.Using NGS strategies, we will disentangle the complex genetic architecture of PD and better define the underlying functional variants in disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance and replicated in large cohorts of PD patients also using the unique resources of the GEO-PD Consortium. Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian randomization, and gene-environment interaction studies. To validate genetic risk variants, functional studies on patient biomaterial will be performed based on (i) the unique expertise for fibroblasts- and iPSC-derived cellular models of PD and (ii) a large repository of biomaterials from carriers of PD-associated mutations. Established readouts allow to study functional effects of identified genetic risk factors and will be used to assign novel disease genes and risk variants to defined pathogenic pathways. Moreover patient-based cellular models will be challenged with environmental risk factors identified as modulators of disease.