Identification of susceptibility genes for Essential Tremor

特发性震颤易感基因的鉴定

• 批准号: 8329627
• 负责人: LORRAINE N CLARK
• 金额: $ 62.84万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329627
• 关键词: Accounting; Address; Affect; Age; Animal Genetics; Animal Model; Area; Bioinformatics; Cell model; Child; Clinical; Clinical assessments; Custom; DNA; DNA Resequencing; Data; Diagnostic; Disease; Dystonia; Elderly; Essential Tremor; Etiology; Evaluation; Familial Tremors; Family; Family member; First Degree Relative; Frequencies; Gene Mutation; Generations; Genes; Genetic; Genetic Models; Genotype; Hereditary Disease; Heterogeneity; Human; Individual; Life; Link; Linkage Disequilibrium; Maps; Methods; Motor Manifestations; Mutation; Parents; Participant; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Population; Predisposition; Prevalence; Publishing; Reading; Recruitment Activity; Relative (related person); Reporting; Risk; Sampling; Scanning; Siblings; Signal Transduction; Susceptibility Gene; Time; Tremor; Twin Studies; Universities; Validation; Variant; Venous blood sampling; base; early onset; epidemiology study; genetic epidemiology; genetic linkage analysis; innovation; nervous system disorder; proband

DESCRIPTION (provided by applicant): Essential tremor (ET) is among the most common neurological diseases, with a prevalence (age >40 years) estimated to be 4.0% and prevalence in advanced age (>90 years) exceeding 20.0%. The underlying pathogenesis remains poorly understood and, as a consequence, current medications are empiric and of limited efficacy. There are only two front-line medications, a situation that has not changed in more than 30 years, and one in two patients simply stops these medications due to poor efficacy. The foremost obstacle to the study of pathogenesis is the absence of an animal (genetic) model for this disease. ET (often referred to as "familial tremor"), is generally regarded as a highly-genetic disorder, with physicians commonly seeing families with affecteds over multiple generations, and twin studies showing high concordance among monozygotes. Despite this, as of 2010, genetic studies have not advanced to the point where susceptibility genes have been identified. Previously published studies of linkage in families suggest that susceptibility loci contribute to the etiology of ET. In the current application we will build on previous studies and propose to use a linkage and resequencing approach to identify susceptibility genes for familial early-onset (<40 years) ET. To overcome the problems associated with previously published genetic studies of ET, which did not use strict phenotype definition in assigning affectedness status, we will use strict diagnostic criteria of 'definite' or 'probable' ET for inclusion of probands and affected individuals in families and further restrict our inclusion to individuals with pure ET (i.e. no dystonia) to reduce heterogeneity and to increase our power to detect a linkage signal. We will also focus on multiplex and multigenerational early onset ET families. To date we have already identified 96 families with an affected proband and >2 living first-degree relatives with ET and in 74 (77%) of families, the proband's age at onset was <40 years.

描述（申请人提供）：特发性震颤（ET）是最常见的神经系统疾病之一，患病率（年龄 >40 岁）估计为 4.0%，高龄（>90 岁）患病率超过 20.0%。其潜在的发病机制仍然知之甚少，因此，目前的药物治疗都是经验性的，疗效有限。一线药物只有两种，这种情况30多年来没有改变，有两分之一的患者因疗效不佳而干脆停止使用这些药物。发病机制研究的最大障碍是缺乏该疾病的动物（遗传）模型。 ET（通常称为“家族性震颤”）通常被认为是一种高度遗传性疾病，医生通常会看到多代受累的家庭，双胞胎研究显示单合子之间的高度一致性。尽管如此，截至2010年，遗传学研究尚未进展到已确定易感基因的程度。先前发表的家族连锁研究表明，易感位点有助于 ET 的病因学。在当前的应用中，我们将在以前的研究的基础上，提出使用连锁和重测序方法来识别家族性早发（<40岁）ET的易感基因。为了克服与先前发表的 ET 遗传学研究相关的问题，这些研究在分配影响状态时没有使用严格的表型定义，我们将使用严格的“确定”或“可能”ET 诊断标准来将先证者和受影响的个体纳入家庭和进一步将我们的纳入范围限制为纯 ET（即无肌张力障碍）的个体，以减少异质性并增加我们检测连锁信号的能力。我们还将重点关注多重和多代早发 ET 家族。迄今为止，我们已经确定了 96 个家庭中存在受累先证者和超过 2 位活着的患有 ET 的一级亲属，并且在 74 个（77%）家庭中，先证者的发病年龄 <40 岁。