Identifying determinants of reduced penetrance by analysis of mutation carriers and by age-at-onset analyses in Parkinson s disease
通过帕金森病突变携带者分析和发病年龄分析确定外显率降低的决定因素
基本信息
- 批准号:318860764
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Units
- 财政年份:2016
- 资助国家:德国
- 起止时间:2015-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
帕金森病(PD)的发病率降低可以表现为致病突变携带者终身无病。这种现象已经在基因LRRK 2、GBA、Parkin、PINK 1和VPS 35中的致病性PD突变的携带者中描述。此外,发病年龄(AAO)的延迟代表了年龄依赖性疾病(如PD)发病率降低的另一个例子。在这两种情况下,潜在的遗传或环境/生活方式修饰剂导致减少的遗传率在很大程度上仍然是难以捉摸的,这至少可以部分归因于缺乏仔细招募和彻底的表型队列与可用的DNA样本。因此,项目P7的总体目标是使用ProtectMove联盟可用的仔细表征的、主要基于人群的多中心队列来识别和进一步表征PD中的抗肿瘤修饰剂。具体来说,我们将寻找遗传和环境/生活方式因素在PD中,减少致病突变的发生率或延迟AAO。首先,我们将通过使用NeuroChip或ExomeChip内容筛选ProtectMove PD病例对照队列中的约21,400名个体来识别已知致病突变的携带者(目标1)。未受影响的携带者将系统地与受影响的突变携带者进行比较,重点关注基于全基因组微阵列和环境/生活方式暴露的数据的遗传修饰剂,以及遗传和环境/生活方式因素与PD状态之间的相互作用(目标2)。在另一组分析中,将在约6,000例PD病例中研究AAO的遗传和环境/生活方式调节剂(目标3)。我们将在ProtectMove队列中进一步评估已发现的抗逆转录病毒修饰遗传变异对临床和临床前疾病特征的影响,同时还将在独立数据集中验证我们的结果(目标4)。最后,我们将通过在PD、肌张力障碍(DYT)和X连锁肌张力障碍-帕金森综合征(XDP)之间进行交叉表型分析来研究AAO遗传决定因素的重叠(目标5)。领导这个项目的是两名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的结果相结合。此外,将在第四至第六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。
项目成果
期刊论文数量(0)
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Professorin Dr. Inke Regina Koenig其他文献
Professorin Dr. Inke Regina Koenig的其他文献
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{{ truncateString('Professorin Dr. Inke Regina Koenig', 18)}}的其他基金
Statistische Analyse des X-Chromosoms in genetischen Assoziationsstudien
遗传关联研究中X染色体的统计分析
- 批准号:
185454350 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Research Grants
Biometrical support for the priority program "Immune and Metabolic Modulation induced by severe Tissue Trauma" and data mining approaches for the identification of disease associated single nucleotide polymorphismus (SNPs)
对优先计划“严重组织创伤引起的免疫和代谢调节”的生物识别支持以及用于识别疾病相关单核苷酸多态性(SNP)的数据挖掘方法
- 批准号:
16852967 - 财政年份:2005
- 资助金额:
-- - 项目类别:
Priority Programmes
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