Identification of Susceptibility Genes for Essential Tremor

 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%。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Geneti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。尽管它的患病率非常高，但我们仍然对易患ET的基因知之甚少。在R01NS073872(9/30/11-8/31/14)的当前资助期间，我们对52个使用严格表型定义(明确和可能的ET)的纯ET家系进行了连锁扫描，提供了与6号染色体(6p24)短臂连锁的证据(LOD评分3.013)。在使用稍微不那么严格的表型定义的分析中，也有几个额外的有希望的线索，在另外五个染色体区域检测到连锁的证据(LOD和GT；3)。使用pVAAST对52个早发性ET家系的WES数据进行分析，也发现了候选ET基因，这些基因在全基因组范围内显著，并且位于具有显著LOD得分的连锁区间内(&gt；3.0)。尽管有一个有限的3年资助窗口(9/30/11-8/31/14)，但在3.2年的时间点上，我们已经完成了目标并确定了ET候选基因。我们与这些家庭的经验有助于进一步认识到临床材料的复杂性，并强调艰苦的临床表型鉴定以及数据分析的替代方法的首要重要性，每一种方法都对成功的努力至关重要。在R01 NS073872竞争延续的A1重新提交中，我们做出了几项实质性更改。我们已经将基于家庭的发现和复制数据集的大小增加了两倍，从而利用了ET社区和收集ET家庭的所有学术中心的所有可用资源，达到了史无前例的1500名受试者的样本规模。我们将仔细标准化所有地点的表型，并采用创新的方法，包括全基因组测序、连锁分析和新的分析方法。我们提出了三个具体的目标：目标1：大幅增加发现数据集中的纯ET家族的样本量，并在复制数据集中重新表型和招募新的纯ET家族。目的：对150个ET家系进行遗传分析，以确定和复制ET的遗传位点，并寻找新的ET基因。目的3：在一个独立的基于家系的重复样本中复制和验证研究结果，并在整个样本中进行基因-表型相关性。

 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%. 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-geneti disorder, with physicians commonly seeing families with affecteds over multiple generations, and twin studies showing high concordance among monozygotes. Despite its extraordinarily high prevalence, we still know almost nothing about genes that predispose individuals to develop ET. During the current funding period of R01 NS073872 (9/30/11 - 8/31/14), our linkage scan in 52 `pure' ET families, which used a stringent phenotype definition (definite and probable ET), provides evidence for linkage to the short arm of chromosome 6 (6p24)(LOD score 3.013). There are also several additional promising leads in analyses that used slightly less stringent phenotype definition, with evidence of linkage (LOD>3) detected in five additional chromosomal regions. Analysis of WES data using pVAAST from 52 early onset ET families has also identified candidate ET genes that are genome wide significant and that are located within linkage intervals with significant LOD scores (>3.0). Despite a limited 3- year funding window (9/30/11 - 8/31/14), at the 3.2 year point, we have completed the aims and have identified ET candidate genes. Our experience with these families has served to further our appreciation of the complexity of the clinical material and to underscore the prime importance of painstaking clinical phenotyping as well as alternative approaches to data analysis, each of which is critical to a successful endeavor. In this A1 resubmission of the competing continuation of R01 NS073872, we have made several substantive changes. We have tripled the size of both the family-based discovery and replication datasets, thereby using all of the available resources of the ET community and all of the academic centers who collect ET families to arrive at the unprecedented sample size of 1,500 subjects. We will carefully standardize phenotyping across all sites and employ innovative methods including whole genome sequencing together with linkage analysis and novel analytic methods. We propose three Specific Aims: AIM 1: To greatly increase the sample size of `pure' ET families in the discovery dataset, and rephenotype and recruit new `pure' ET families in the replication dataset. Aim 2: To perform genetic analyses of 150 ET families to confirm and replicate ET genetic loci in addition to identifying new ET genes. AIM 3: To replicate and validate findings in an independent family-based replicate sample, and to perform genotype-phenotype correlations in the entire sample.