Developmental stuttering: Population-based genetic discovery

摘要 口吃是一种发育性语言障碍，在所有的口吃患者中， 复杂遗传的交流障碍虽然全世界人口的持续流行 发展性口吃是1%，5-6%的儿童发展性口吃， 口吃（11-14%）在澳大利亚的儿童中有报道。与该疾病风险相关的基因 尚未在非血缘关系的一般人群中确定;很少有研究对 发育性口吃的遗传易感性，每一个都集中在来自遗传分离株的家族中， 血缘关系的水平。尚未进行大规模、强有力、基于人群的研究， 检测与口吃风险相关的基因组变异，因此对口吃风险知之甚少。 发育性口吃的分子基础为了弥补这一知识差距，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再收集2,000份唾液 来自被诊断患有发展性口吃的参与者的样本，他们接受了来自全球的治疗， 在英国、澳大利亚、爱尔兰和美国都有公认的口吃中心。我们还将通过 一个创新的社交媒体招募活动，将我们的发展性口吃病例样本 到3000。所有参与者都将得到经过语言和语言培训的专家的诊断 病理学，详细记录发育性口吃的严重程度和病史的密集表型数据，以及 将包括在使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，提供一个全基因组的骨干，将被归因于 所有样本中的最新全基因组参考面板，允许对常见变异进行稳健测试 关联全基因组，第二，Aim 3）将进行全外显子组测序，以选择性地 捕获所有蛋白质编码基因内的变异，提供了一个理想的基因区域的画像， 不成比例地负担着罕见的功能性变异。至少有5,000个基于人口的祖先- 将从范德比尔特中选择无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 使用这些对照数据集进行回顾和分析将为我们全面的遗传分析提供动力， 恢复和持续发展口吃，产生了非常丰富的，公共资源的结果， 未来的遗传、功能和翻译研究。目标4）我们将确定额外的1,000个发展项目， 语言障碍病例和1,000名祖先匹配的对照者，通过BioVU的电子病历， 复制最重要的发现。这些互补的方法将共同导致识别和验证 的基因和途径，有助于发展性口吃的风险，提供了重要的见解， 一种常见的、高度遗传的、通常使人衰弱的疾病，目前其生物学病因尚不清楚。

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.