Identification of susceptibility genes for Essential Tremor

描述（由申请人提供）：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%。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。一线药物只有两种，这种情况30多年来没有改变，每两名患者中就有一名因疗效不佳而停止使用这些药物。发病机制研究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，医生通常会看到多代受影响的家庭，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，遗传学研究尚未发展到确定易感基因的程度。以前发表的研究连锁的家庭表明，易感基因座有助于ET的病因。在本申请中，我们将建立在以前的研究，并建议使用连锁和重测序的方法来确定家族性早发性（<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，该研究在指定受影响状态时没有使用严格的表型定义，我们将使用严格的诊断标准“明确的”或“可能的”ET纳入先证者和受影响的个人在家庭中，并进一步限制我们的纳入个人与纯粹的ET（即无肌张力障碍）以减少异质性并增加我们检测连锁信号的能力。我们还将重点关注多重和多代早发性ET家庭。到目前为止，我们已经确定了96个家庭，其中有一个受影响的先证者和2个以上的一级亲属患有ET，74个（77%）家庭的先证者发病年龄<40岁。 公共卫生相关性：ET是一种高度遗传性疾病，是人类震颤的最常见原因，影响了全球大量个体。目前的治疗，这是大部分不成功的，是经验。基于对疾病发病机制的理解的治疗是必要的，但缺乏任何确定的基因和由此产生的缺乏动物模型，是阻碍这些研究的最大障碍。

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. PUBLIC HEALTH RELEVANCE: ET, a highly genetic disorder, is the most common cause of tremor in humans, affecting large numbers of individuals worldwide. Current treatments, which are largely unsuccessful, are empiric. Therapies based on an understanding of disease pathogenesis are needed, yet the absence of any identified genes and the resultant lack of an animal model, is the foremost obstacle standing in the way of these studies.