Understanding the biology of language impairment through whole genome sequencing

 描述(申请人提供)：口语是人类行为的一种近乎普遍的特征，它将个人绑定到社会群体中，并为人际互动、学习、解决问题和商业提供重要工具。大多数儿童很快就学会了他们所在社区的口语，而且他们自己或他们的照顾者几乎没有刻意的努力。然而，并不是所有的孩子都同样成功地做到了这一点。语言障碍(LI)是导致这一社会问题的一个因素，它是一种神经发育状况，会导致儿童在其他方面发育正常的情况下出现语言缺陷(即排除了自闭症或听力障碍等其他状况)。李灿对社会关系、就业和心理健康都有深远而持久的影响。众所周知，LI具有大量的基因成分，但过去十年的基因研究中使用的技术只能涉及到少数几个特定的基因。我们建议使用全基因组测序(WGS)来制作迄今为止最全面的语言障碍和语言熟练个体的遗传变异目录(目标1)。使用这个目录，我们将使用计算方法来推断每个基因变异最可能的功能影响。这些假定的功能变异将被组合在一起，形成在LI中可能起作用的途径和基因集，我们将测试(目标2)病例(语言受损)和对照(语言熟练)中功能遗传变异的丰富程度。此外，我们将通过使用NOVE测试来研究潜在功能非编码遗传变异的作用，该检验用于在调节标志附近的遗传变异的位置丰富，例如语言相关转录因子FOXP2的基因组结合位点。最后，我们将检验这一假设，即李与一些自闭症谱系障碍(ASD)患者存在语言缺陷的遗传基础相同。这将通过执行基因网络分析来实现，该网络分析寻找功能变异(网络模块)集中遗传负担的区域。基于LI基因变异的模块将与基于ASD变异的模块进行比较，根据它们的接近和重叠的重要性。这一分析将在分子水平上进一步阐明这些具有相似临床特征的疾病之间的关系。这个项目有可能改变LI的遗传学，并阐明其潜在的生物学和与其他神经发育疾病的联系。我们将对李和ASD之间的任何共同遗传责任有更具体的了解。此外，这将是第一个使用WGS的LI遗传学研究，目标是综合分析所有主要的遗传变异模式(单核苷酸变异、Indels和结构变异)，同时捕捉完整的频谱-稀有和常见的等位基因。通过增加我们对LI中起作用的基因的理解，我们将更接近于能够使用基因发现作为证据来支持早期干预以改善结果。

 DESCRIPTION (provided by applicant): Spoken language is a near universal feature of human behavior that binds individuals into social groups and provides vital tools for interpersonal interaction, learning, problem solving and commerce. Most children acquire the spoken language of their community quickly and with little conscious effort on their part or on the part of their caregivers. However, not all children accomplish this with equal success. Language impairment (LI), one contributor to this societal problem, is a neurodevelopmental condition that leads to linguistic deficits in children where development is otherwise normal (i.e. other conditions such as autism or hearing impairment have been ruled out). LI can have profound and lasting effects on social relations, employment, and mental health. LI is known to have a substantial genetic component, but the technologies used in the past decade of genetic research have only been able to implicate a few specific genes. We propose to use whole genome sequencing (WGS) to produce the most comprehensive catalog to date of genetic variation in language impaired and language proficient individuals (aim 1). Using this catalog, we will use computational approaches to infer the most likely functional impact for each genetic variant. These putatively functional variants will be grouped together into pathways and gene sets for which there is a plausible role in LI, and we will test (aim 2) for enrichment of functionl genetic variation in cases (language impaired) vs. controls (language proficient). Furthermore, we will investigate the role of potentially functional non-coding genetic variation by using a nove test for positional enrichment of genetic variation near regulatory landmarks, such as genomic binding sites of the language-associated transcription factor FOXP2. Finally, we will test the hypothesis that LI shares a genetic basis with the language deficits present in some individuals with autism spectrum disorders (ASDs). This will be accomplished through performing a gene network analysis that looks for regions of concentrated genetic burden of functional variants (network modules). Modules based on LI genetic variants will be compared with modules based on ASD variants, in terms of the significance of their proximity and overlap. This analysis will further illuminate, on a molecular level, the relationship between these conditions that share some similar clinical features. This project has the potential to transform the genetics of LI and illuminate its underlying biology and connection to other neurodevelopmental conditions. We will gain a more concrete understanding of any shared genetic liability between LI and ASD. Further, this would be the first LI genetics study to use WGS, with the goal of an integrated analysis of all major modes of genetic variation (single nucleotide variants, indels, and structura variants) while capturing the full frequency spectrum - rare and common alleles alike. By increasing our understanding of the genes at play in LI, we will move closer to being able to use genetic findings as evidence to support early interventions for improved outcomes.