Developmental stuttering: Population-based genetic discovery

摘要 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 复杂遗传的沟通障碍。虽然世界范围内的人口流行率持续 发育性口吃为1%，5%-6%的儿童发育性口吃，患病率增加 据报道，澳大利亚有儿童口吃(11%-14%)。与疾病风险相关的基因有 尚未在非血缘关系的普通人群中确定；很少有关于 发育性口吃的遗传易感性，每个都集中在高基因分离的家系中 血缘关系的等级。大规模、有充足动力的、以人口为基础的研究尚未开展到 检测与口吃风险相关的基因组变异，结果是对 发育性口吃的分子基础。为了解决这一知识差距，我们提出了以下建议 明确的目标。目标1)我们将在现有研究项目的基础上，额外收集2,000份唾液 来自全球接受治疗的被诊断为发育性口吃的参与者的样本 位于英国、澳大利亚、爱尔兰和美国的公认口吃中心。我们还将通过 一项创新的社交媒体招聘活动带来了我们发展性口吃病例的全部样本 到3000人。所有参与者都将得到经过语音和语言培训的专家的诊断确认 病理，记录了详细说明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)第一，多种族基因分型 阵列(Mega)将捕获200多万个变种，提供全基因组的主干，这将归因于 所有样本中最新的全基因组参考板，允许对常见变异进行可靠的测试 关联全基因组，第二，目标3)整个外显子组测序将选择性地 捕捉所有蛋白质编码基因的变异，提供理想的基因区域画像 不成比例地背负着稀有和功能变异的负担。至少5000个以人口为基础的祖先- 没有已知言语和语言障碍病史的匹配对照将从Vanderbilt选择 大学的BioVU DNA数据库以及社区动脉粥样硬化风险(ARIC)研究。接合 回顾和分析使用这些对照数据集将支持我们的全面遗传分析 恢复和持续发展的口吃，为以下方面产生了极其丰富的公共资源 未来的遗传、功能和翻译研究。目标4)我们将确定另外1,000个开发项目 通过BioVU的电子病历治疗言语障碍病例和1,000名祖先匹配的对照 复制最重要的发现。这些相辅相成的方法将共同导致识别和验证 导致发育性口吃风险的基因和途径，提供了非常重要的洞察 一种常见的、高度可遗传的、经常使人衰弱的疾病，目前其生物病因尚不清楚。

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.