Identification of genetic and metabolomic markers influencing dystonia

 描述(申请人提供)：作为第三种最常见的运动障碍，口吃困难总共影响着全球200多万人。尽管它们的流行率很高，但它们的生物学根源在很大程度上是未知的。家族性研究表明遗传和环境因素都有影响，然而，在已确定的病例中，没有特定的遗传变异或环境因素是导致很大比例的原因。外周血液的代谢特征会受到环境和遗传因素的影响，也会受到个体生理状况的影响。研究代谢组谱是了解连接环境、基因组学和口腔动力障碍发生发展的生物系统的重要组成部分。对肌张力障碍的分子和系统的了解将有助于提高临床的准确诊断和有效治疗。以前对口音障碍的全基因组关联研究受到样本量较小和缺乏稀有变异的覆盖范围的限制。目前还没有对口吃困难的代谢学研究来研究小分子的作用。在这项研究中，我们将使用高通量基因组和代谢组学方法来有效地调查170多万个遗传变异和20,000多个代谢组学特征之间的关系。我们将对候选基因进行有针对性的分析，并在美国现有的最大样本肌张力障碍患者中进行与肌张力障碍相关的基因组和代谢组学搜索。

 DESCRIPTION (provided by applicant): As the third most common movement disorder, dystonias collectively affect more than 2 million people worldwide. Despite their high prevalence, their biological roots are largely unknown. Both genetic and environmental influences are suggested in familial studies, however, no specific genetic variants or environmental factors are responsible for a significant proportion of identified cases. Metabolomic profile of peripheral blood can be influenced by environmental and genetic factors, as well as physiological condition of an individual. Studying the metabolomic profile is an important component to understand the biological systems linking the environment, genomics and the development of dystonias. Molecular and system understanding of the dystonias would enhance the clinical practice of accurate diagnosis and effective treatment. Previous genome-wide association studies of the dystonias were limited by smaller sample size and lack of coverage of rare variants. No metabolomic study of the dystonias has been conducted to investigate the role of small molecules. In this study, we will use a high-throughput genomic and metabolomic approach to effectively investigate relationships between over 1.7 million genetic variations and over 20,000 metabolomic features. We will conduct targeted analyses of candidate genes, as well as agnostic searches for any genomic and metabolomic associations with the dystonias in the largest sample of dystonia patients available in the US.