Identifying determinants of reduced penetrance by analysis of mutation carriers and by age-at-onset analyses in Parkinson s disease

帕金森病（PD）的外显率降低可以表现为致病突变携带者终生无疾病。这种现象已经在LRRK2、GBA、Parkin、PINK1和VPS35基因的致病PD突变携带者中得到描述。此外，发病年龄延迟（AAO）是PD等年龄依赖性疾病外显率降低的另一个例子。在这两种情况下，导致外显率降低的潜在遗传或环境/生活方式修饰因素在很大程度上仍然难以捉摸，这至少可以部分归因于缺乏精心招募的、具有可用DNA样本的彻底表型队列。因此，P7项目的总体目标是利用ProtectMove联盟提供的精心表征的、主要基于人群的多中心队列，识别和进一步表征PD的外显率修饰因子。具体来说，我们将寻找PD中降低致病突变外显率或延迟AAO的遗传和环境/生活方式因素。首先，我们将使用NeuroChip或ExomeChip内容，通过筛选来自ProtectMove PD病例对照队列的约21,400名个体，确定已知致病突变的携带者（目标1）。未受影响的携带者将与受影响的突变携带者进行系统比较，重点关注基于全基因组微阵列和环境/生活方式暴露数据的遗传修饰因子，以及遗传和环境/生活方式因素之间与PD状态的相互作用（目标2）。在另一组分析中，将在大约6000例PD病例中调查AAO的遗传和环境/生活方式改变因素（目标3）。我们将在ProtectMove队列中进一步评估发现的外显子修饰遗传变异对临床和临床前疾病特征的影响，同时在独立数据集中验证我们的结果（目标4）。最后，我们将通过PD、肌张力障碍（DYT）和x连锁肌张力障碍-帕金森病（XDP）之间的交叉表型分析来研究AAO遗传决定因素的重叠（目的5）。领导这个项目的是两位在生物统计学和遗传流行病学方面具有丰富经验和良好出版记录的pi。该项目是ProtectMove的一个组成部分，因为所有可用的ProtectMove队列将用于生成数据，分析将与其他研究单位项目获得的结果相结合。此外，将在第4-6年期间进行的后续精细绘图和功能表征将利用通过研究股建立的合作。

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.