Identification of Susceptibility Genes for Essential Tremor

特发性震颤易感基因的鉴定

基本信息

批准号：
9117640
负责人：
LORRAINE N CLARK
金额：
$ 117.89万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9117640
关键词：
6p24 Affect Age American Animal Genetics Animal Model Ashkenazim Biometry Blood specimen Candidate Disease Gene Chromosomes, Human, Pair 6 Clinical Collaborations Collection Communities Complex Data Data Analyses Data Set Disease Disease model Elderly Essential Tremor Familial Tremors Family Family member Funding Future Generations Genes Genetic Genetic Models Genome Genotype Goals Health Hereditary Disease High Prevalence Human Individual Intention Tremor Letters Libraries Medicine Methods Motor Manifestations Mutation New York Parents Pathogenesis Patients Pharmaceutical Preparations Phenotype Physicians Preparation Prevalence Recruitment Activity Reporting Research Personnel Resources Sample Size Sampling Scanning Severities Site Statistical Data Interpretation Susceptibility Gene Targeted Resequencing Testing Tremor Twin Studies Universities Variant age difference arm base clinical material clinical phenotype college design early onset effective therapy experience family structure follower of religion Jewish gene discovery genetic analysis genetic linkage analysis genetic pedigree genome sequencing genome-wide high standard innovation nervous system disorder novel offspring proband rare variant segregation tool transcriptomics whole genome

项目摘要

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.

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）发病率仍超过 20%。人们对其知之甚少，因此，目前的药物都是经验性的，疗效有限。一线药物只有两种，这种情况 30 多年来一直没有改变，二分之一的患者只是停止使用这些药物。 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，其发病机制研究的首要障碍是缺乏动物（遗传）模型。医生经常看到多代受累的家庭，双胞胎研究显示单合子之间的高度一致性，尽管其患病率非常高，但在目前的资助期间，我们对易患 ET 的基因几乎一无所知。 R01 NS073872 (9/30/11 - 8/31/14)，我们对 52 个“纯”ET 家族进行的连锁扫描，使用了严格的表型定义（确定的和可能的 ET），为与染色体短臂的连锁提供了证据6 (6p24)（LOD 评分 3.013）在使用稍微不太严格的表型定义的分析中还有一些其他有希望的线索，并有关联的证据。 (LOD>3) 使用 pVAAST 对 52 个早发 ET 家族的 WES 数据进行分析，还发现了候选 ET 基因，这些基因在全基因组范围内具有显着性，并且位于具有显着 LOD 分数 (>3.0) 的连锁区间内。尽管 3 年资助窗口有限（2011 年 9 月 30 日 - 2014 年 8 月 31 日），但在 3.2 年时，我们已经完成了目标并确定了 ET 候选基因。这些家庭的经验进一步加深了我们对临床材料复杂性的认识，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重要性，其中每一项对于 A1 重新提交的成功都至关重要。在 R01 NS073872 的竞争性延续中，我们做出了一些实质性的改变，我们将基于家族的发现和复制数据集的大小增加了两倍，从而利用了 ET 社区的所有可用资源。所有收集 ET 家族的学术中心将仔细标准化所有站点的表型分析，并采用包括全基因组测序以及连锁分析和新颖分析方法在内的创新方法。：目标 1：大幅增加发现数据集中“纯”ET 家族的样本量，并在复制数据集中重新表型并招募新的“纯”ET 家族。目标 2：进行遗传分析。分析 150 个 ET 家族，以确认和复制 ET 基因位点，并鉴定新的 ET 基因。目标 3：在独立的基于家族的复制样本中复制和验证研究结果，并在整个样本中进行基因型-表型相关性。