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Developmental stuttering: Population-based genetic discovery

发育性口吃：基于群体的遗传发现

基本信息

批准号：
10455451
负责人：
Jennifer Below
金额：
$ 72.74万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455451
关键词：
5 year old Address Adolescent Adult Adult Stuttering Affect Age Age-Years Atherosclerosis Risk in Communities Australia Biochemical Pathway Biological Candidate Disease Gene Characteristics Child Code Communication Communication impairment Complex Computerized Medical Record Consanguinity DNA DNA Databases Data Data Set Development Developmental Stuttering Diagnosis Diagnostic Disease Documentation Emotions England Enrollment Enzymes Etiology Exhibits Family Family history of Funding Future General Population Genes Genetic Genetic Predisposition to Disease Genetic study Genomics Genotype Heritability High Prevalence Hospitalization Incidence Individual International Ireland Joints Knowledge Language Lead Location Longevity Lysosomes Media Campaign Molecular Motor Movement Mutation Occupations Participant Pathway interactions Patients Performance at work Persons Pharmacologic Substance Population Population Study Portraits Predisposition Prevalence Prevention Production Proteins Publishing Recording of previous events Recovery Recurrence Relative Risks Reporting Research Research Design Resources Risk Sampling Schools Severities Siblings Signal Transduction Specialist Speech Speech Disorders Speech Therapy Speech-Language Pathology Students Stuttering Testing Therapeutic Time Training Universities Validation Variant Vertebral column base case history cognitive testing cohort data resource design disorder risk exome exome sequencing experience family genetics genetic analysis genetic architecture genetic signature genetic variant genome wide association study genome-wide high risk improved innovation insight language impairment low socioeconomic status male multi-ethnic outreach phenotypic data population based proband programs rare variant recruit reference genome saliva sample sex social media translational study treatment center whole genome

项目摘要

ABSTRACT Stuttering is a developmental speech disorder that has one of the highest familial recurrence rates among communication disorders with complex inheritance. While worldwide population prevalence of persistent developmental stuttering is 1%, and 5-6% of children stutter developmentally, an increased prevalence of stuttering (11-14%) has been reported in children in Australia. Genes associated with risk of the disorder have yet to be identified in the non-consanguineous general population; few studies have been conducted on the genetic susceptibility of developmental stuttering, each focusing on families from genetic isolates with high levels of consanguinity. Large-scale, well-powered, population-based studies have not yet been undertaken to detect genomic variants associated with stuttering risk, and as a result extremely little is known about the molecular underpinnings of developmental stuttering. To address this gap in knowledge we propose the follow specific aims. Aim 1) We will build on our existing research program by collecting an additional 2,000 saliva samples from participants diagnosed with developmental stuttering who receive treatment from globally recognized stuttering centers located in England, Australia, Ireland, and the USA. We will also collect through an innovative social media recruitment campaign bringing our total sample of developmental stuttering cases to 3,000. All participants will have diagnoses confirmed by specialists trained in speech and language pathology, dense phenotypic data recorded detailing severity and case history of developmental stuttering, and will be included in genetic analyses utilizing two primary approaches. Aim 2) First, Multi-Ethnic Genotyping Arrays (MEGA) will capture over 2 million variants, providing a genome-wide backbone that will be imputed to the latest whole genome reference panel in all samples, allowing for robust tests of common variant association genome-wide, and second, Aim 3) whole exome sequencing will be performed to selectively capture variation within all protein-coding genes, providing an ideal portrait of the genic regions that are disproportionately burdened with rare and functional variation. A minimum of 5,000 population-based ancestry- matched controls with no known history of speech and language impairment will be selected from Vanderbilt University's BioVU DNA databank as well as the Atherosclerosis Risk in Communities (ARIC) Study. Joint recalling and analysis using these control datasets will power our comprehensive genetic analyses of recovered and persistent developmental stuttering, generating an extremely rich, public resource of results for future genetic, functional, and translational studies. Aim 4) We will identify an additional 1,000 developmental speech disorder cases and 1,000 ancestry-matched controls via electronic medical records in BioVU for replication of top findings. Together, these complementary approaches will lead to identification and validation of genes and pathways contributing to risk of developmental stuttering, providing significant insight into a very common, highly heritable, and often debilitating disorder that today has a largely unknown biological etiology.

抽象的口吃是一种发育性言语障碍，是家族复发率最高的疾病之一。具有复杂遗传性的沟通障碍。虽然全球人口持续存在发育性口吃的比例为 1%，5-6% 的儿童存在发育性口吃，这种现象的患病率有所增加据报道，澳大利亚儿童有口吃（11-14%）。与该疾病风险相关的基因尚未在非近亲结婚的一般人群中确定；对此进行了很少的研究发育性口吃的遗传易感性，每个都集中于具有高遗传分离株的家庭血缘关系的等级。尚未开展大规模、有力、以人群为基础的研究检测与口吃风险相关的基因组变异，因此人们对它知之甚少发育性口吃的分子基础。为了解决这一知识差距，我们提出以下建议具体目标。目标 1) 我们将在现有研究计划的基础上额外收集 2,000 份唾液来自全球接受治疗的被诊断患有发育性口吃的参与者的样本位于英格兰、澳大利亚、爱尔兰和美国的公认口吃中心。我们还将通过收集创新的社交媒体招聘活动带来了我们的发育性口吃案例的全部样本到 3,000。所有参与者都将得到经过言语和语言培训的专家的诊断确认病理学、记录的密集表型数据，详细说明发育性口吃的严重程度和病例史，以及将被纳入利用两种主要方法的遗传分析中。目标 2) 首先，多种族基因分型阵列 (MEGA) 将捕获超过 200 万个变异，提供全基因组主干，将归因于所有样本中最新的全基因组参考面板，允许对常见变异进行稳健的测试全基因组关联，第二，目标 3）将选择性地进行全外显子组测序捕获所有蛋白质编码基因内的变异，提供基因区域的理想肖像不成比例地承受着罕见的功能变异。至少有 5,000 个人口血统 - 将从范德比尔特大学选择没有已知言语和语言障碍史的匹配对照大学的 BioVU DNA 数据库以及社区动脉粥样硬化风险 (ARIC) 研究。联合的使用这些控制数据集的回忆和分析将为我们的全面遗传分析提供支持恢复和持续的发育性口吃，产生了极其丰富的公共成果资源未来的遗传、功能和转化研究。目标 4) 我们将确定另外 1,000 个发展型通过 BioVU 中的电子病历记录言语障碍病例和 1,000 个血统匹配的对照复制最重要的发现。这些互补的方法共同将导致识别和验证导致发育性口吃风险的基因和途径，提供了重要的见解一种常见的、高度遗传性的、常常使人衰弱的疾病，目前其生物学病因学基本上未知。