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

尽管在帕金森氏病(PD)相关基因的鉴定方面取得了进展，但我们对PD的理解仍然存在明显的差距。因此，我们提出了一种基于(I)独特的家系集合和(Ii)大量散发性帕金森病患者队列的综合方法，用于(Iii)基因研究和(Iv)环境调节剂的评估，这将转化为(V)功能验证研究。使用NGS策略，我们将解开帕金森病复杂的遗传结构，并更好地定义与疾病相关的Gwas基因座的潜在功能变异。新发现的遗传变异被筛选出致病相关性，并利用GEO-PD联盟的独特资源在PD患者的大量队列中复制。随后对疾病修饰物的评估包括两种互补的方法：孟德尔随机化和基因-环境相互作用研究。为了验证遗传风险变异，对患者生物材料的功能研究将基于(I)帕金森病成纤维细胞和IPSC衍生的帕金森病细胞模型的独特专业知识，以及(Ii)来自帕金森病相关突变携带者的大量生物材料。已建立的读数允许研究已识别的遗传风险因素的功能效应，并将用于将新的疾病基因和风险变量分配给确定的致病途径。此外，以患者为基础的细胞模型将受到环境风险因素的挑战，这些因素被认为是疾病的调节器。

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.