Identification of susceptibility genes for Essential Tremor

特发性震颤易感基因的鉴定

• 批准号: 8520409
• 负责人: LORRAINE N CLARK
• 金额: $ 60.1万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520409
• 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; 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; risk variant

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，其患病率(年龄和40岁)估计为4.0%，高龄(和90岁)的患病率超过20.0%。潜在的发病机制仍然知之甚少，因此，目前的药物是经验性的，疗效有限。只有两种一线药物，这种情况30多年来没有改变，每两名患者中就有一人因疗效不佳而干脆停止这些药物。研究发病机制的最大障碍是缺乏这种疾病的动物(遗传)模型。ET(通常被称为“家族性震颤”)通常被认为是一种高度遗传性疾病，医生通常会在多代人中看到受影响的家庭，双胞胎研究显示单合子之间高度一致。尽管如此，截至2010年，遗传学研究还没有发展到识别易感基因的地步。先前发表的关于家族性连锁的研究表明，易感基因与ET的病因有关。在目前的应用中，我们将建立在以前研究的基础上，并建议使用连锁和重新测序的方法来识别家族性早发(&lt；40年)ET的易感基因。为了克服之前发表的ET遗传学研究中没有使用严格的表型定义来指定受影响状态的相关问题，我们将使用严格的诊断标准“确定的”或“可能的”ET将先证者和受影响的个人包括在家庭中，并进一步限制我们包括患有纯ET的个人(即没有肌张力障碍)，以减少异质性并增加我们检测连锁信号的能力。我们还将关注多胎和多代早发性ET家系。到目前为止，我们已经确认了96个先证者和2个患有ET的一级亲属，其中74个(77%)先证者的发病年龄为&lt；40岁。