Environmental risk factors and gene-environment interactions in ALS risk and progression

 描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种多方面的疾病，几乎可以肯定（最常见）是由遗传风险、环境暴露和随机事件之间的复杂相互作用引起的。人们也越来越认识到，疾病的临床过程是独立于疾病风险的。虽然已经确定了一些疾病进展的遗传决定因素，但对影响疾病进程的环境因素几乎一无所知。这项研究将研究非遗传因素和基因-环境相互作用对ALS疾病进展的影响，并探讨基因-环境相互作用对ALS发病几率的影响。这些目标将通过利用最近成立的ALS和相关疾病治疗开发（CReATe）联盟为我们提供的重要机会来实现，该联盟是NIH资助的罕见疾病临床研究网络（RDCRN）的一部分。我们将在前瞻性和系统性收集的深度表型数据和全基因组测序数据中添加详细的环境暴露数据，CReATe将收集500名ALS患者的数据，并将采用仅病例分析和孟德尔随机化等创新方法来实现我们的特定目标。重要的是，这项工作还将阐明未来有意义地使用通过国家ALS登记处在线门户网站收集的“仅限病例”环境暴露数据的方法。因此，这项工作推进了国家ALS登记处的总体目标，并展望了未来，因为国家ALS登记处的范围可能会扩大到包括纵向数据收集以及生物样本（包括DNA）库。

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a multifaceted disorder that almost certainly arises (most commonly) from a complex interplay between genetic risk, environmental exposure and stochastic events. Increasingly, it is also recognized that the clinical course of disease is determined independently of the risk of disease. And while some genetic determinants of disease progression have been identified, almost nothing is known about the environmental factors that impact the course of disease. This study will examine the influence of non-genetic factors and gene-environmental interactions on ALS disease progression, and will also explore the influence of gene-environmental interactions on the odds of developing ALS. These goals will be accomplished by leveraging the significant opportunity afforded to us by the recent establishment of the Clinical Research in ALS and related disorders for Therapeutic Development (CReATe) Consortium as part of the NIH-funded Rare Diseases Clinical Research Network (RDCRN). We will add detailed environmental exposure data to the prospectively and systematically collected deep phenotypic data and whole genome sequencing data that CReATe will collect on 500 patients with ALS, and will employ innovative approaches such as case-only analyses and Mendelian Randomization to address our specific aims. Importantly, this work will also elucidate an approach for future meaningful use of the `case-only' environmental exposure data being collected through the online portal of the National ALS Registry. This work, therefore, advances of the over-arching aims of the National ALS Registry and looks to the future as the scope of the National ALS Registry potentially broadens to encompass longitudinal data collection as well as banking of biological samples (including DNA).