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（40岁至40岁）估计为4.0%，老年患病率（90岁至90岁）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，每两个患者中就有一个由于疗效不佳而直接停药。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，医生通常会看到家族中有多代人受到影响，双胞胎研究显示同卵之间的高度一致性。尽管如此，截至2010年，遗传研究尚未进展到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，我们将以先前的研究为基础，提出使用连锁和重测序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遗传研究相关的问题，这些研究没有使用严格的表型定义来确定影响状态，我们将使用严格的“确定”或“可能”ET的诊断标准来纳入先证和家庭中受影响的个体，并进一步将我们的纳入限制在纯ET（即无肌张力障碍）的个体中，以减少异质性并提高我们检测连锁信号的能力。我们还将重点关注多代早发性ET家庭。到目前为止，我们已经确定了96个家庭有受影响的先证者和bb20个在世的一级亲属患有ET，在74个（77%）家庭中，先证者的发病年龄小于40岁。

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.