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，但我们对帕金森氏病的认识仍有明显的差距。因此，我们提出了一种基于(i)独特的家庭集合和（ii）散发性PD患者大队列的综合方法，用于（iii）遗传研究和（iv）环境修饰物评估，这些修饰物将转化为(v)功能验证研究。使用NGS策略，我们将解开PD复杂的遗传结构，并更好地定义疾病相关GWAS位点的潜在功能变异。新发现的遗传变异被筛选为致病相关性，并利用GEO-PD联盟的独特资源在PD患者的大型队列中复制。疾病修饰因子的后续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，将基于(i) PD成纤维细胞和ipsc衍生的细胞模型的独特专业知识和（ii） PD相关突变携带者的大型生物材料库，对患者生物材料进行功能研究。已建立的读数允许研究已确定的遗传风险因素的功能影响，并将用于分配新的疾病基因和风险变异，以确定致病途径。此外，基于患者的细胞模型将受到环境风险因素作为疾病调节剂的挑战。

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.