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，患病率（年龄>40岁）估计为4.0%，高龄（>90岁）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。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一致性很高。尽管其发病率非常高，但我们仍然对使个体易患ET的基因几乎一无所知。在R 01 NS 073872的当前资助期内（9/30/11 - 8/31/14），我们在52个“纯”ET家族中进行了连锁扫描，使用了严格的表型定义（明确和可能的ET），提供了与6号染色体短臂（6p 24）连锁的证据（LOD评分3.013）。在使用稍微不太严格的表型定义的分析中也有几个额外的有希望的线索，在五个额外的染色体区域中检测到连锁的证据（LOD>3）。使用来自52个早发性ET家族的pVAAST的WES数据的分析还鉴定了候选ET基因，所述候选ET基因是全基因组显著的并且位于具有显著LOD得分（>3.0）的连锁区间内。尽管有一个有限的3年资助窗口（9/30/11 - 8/31/14），在3.2年的时间点，我们已经完成了目标，并确定了ET候选基因。我们对这些家族的经验有助于我们进一步了解临床材料的复杂性，并强调了艰苦的临床表型分析以及数据分析的替代方法的首要意义，每一种方法都是奋进。在R 01 NS 073872的竞争延续的A1重新提交中，我们做了几个实质性的修改。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，以达到前所未有的1，500名受试者的样本量。我们将仔细标准化所有地点的表型，并采用创新方法，包括全基因组测序以及连锁分析和新的分析方法。我们提出了三个具体目标：目标1：大大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2：对150个ET家系进行遗传学分析，确定和复制ET基因位点，并鉴定新的ET基因。目标3：在独立的基于家系的重复样本中重复和验证结果，并在整个样本中进行基因型-表型相关性分析。

 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.