Understanding the biology of language impairment through whole genome sequencing

通过全基因组测序了解语言障碍的生物学

• 批准号: 9186514
• 负责人: Jacob James Michaelson
• 金额: $ 63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186514
• 关键词: Address; Adult; Affect; Alleles; Autistic Disorder; Behavior; Binding; Binding Sites; Biological; Biology; Caregivers; Catalogs; Child; Child Development; Clinical; Code; Commerce; Communication impairment; Communities; Conscious; Copy Number Polymorphism; Data; Diagnosis; Disease; Early Diagnosis; Early Intervention; Employment; FOXP2 gene; Frequencies; Gene Cluster; Genes; Genetic; Genetic Research; Genetic Variation; Genetic study; Genome; Genomic approach; Genomics; Goals; Heritability; Human; Individual; Interpersonal Relations; Iowa; Knowledge; Language; Language Disorders; Learning; Linguistics; Mental Health; Methods; Molecular; Neurobiology; Nucleotides; Other Genetics; Pathway Analysis; Pathway interactions; Phenotype; Play; Positioning Attribute; Prevalence; Problem Solving; Psychiatry; Quantitative Trait Loci; Recruitment Activity; Research; Resolution; Role; Sampling; Science; Seasons; Technology; Testing; Untranslated RNA; Variant; autism spectrum disorder; base; career; clinical phenotype; cohort; developmental disease; experience; genetic variant; genome sequencing; genome wide association study; hearing impairment; improved; improved outcome; insertion/deletion mutation; language impairment; literacy; member; neuropsychiatry; novel; public health relevance; risk variant; social; social group; success; tool; transcription factor; whole genome

 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.

 描述（由申请人提供）：口语是人类行为的一个近乎普遍的特征，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。大多数儿童很快就能掌握他们社区的口语，他们自己或他们的照顾者几乎没有做出任何有意识的努力。然而，并不是所有的孩子都能同样成功地做到这一点。语言障碍（LI）是造成这一社会问题的一个因素，是一种神经发育状况，导致儿童的语言缺陷，而儿童的发育是正常的（即排除了自闭症或听力障碍等其他状况）。LI可以对社会关系，就业和心理健康产生深远而持久的影响。LI被认为具有相当大的遗传成分，但在过去十年的遗传研究中使用的技术只能涉及一些特定的基因。我们建议使用全基因组测序（WGS）来产生迄今为止语言障碍和语言熟练个体的遗传变异的最全面的目录（目的1）。使用这个目录，我们将使用计算方法来推断每个遗传变异最可能的功能影响。这些功能性变异将被一起分组为在LI中具有合理作用的途径和基因组，并且我们将测试（目的2）病例（语言受损）与对照（语言熟练）中功能性遗传变异的富集。此外，我们将调查潜在的功能性非编码遗传变异的作用，通过使用一个新的测试位置富集的遗传变异附近的监管地标，如基因组结合位点的语言相关的转录因子FOXP 2。最后，我们将测试的假设，LI共享的遗传基础与语言缺陷存在于一些个体与自闭症谱系障碍（ASD）。这将通过进行基因网络分析来实现，该分析寻找功能变体（网络模块）的集中遗传负担区域。基于Ll遗传变体的模块将与基于ASD变体的模块在其接近和重叠的显著性方面进行比较。这项分析将进一步阐明，在分子水平上，这些条件之间的关系，共享一些相似的临床特征。该项目有可能改变LI的遗传学，并阐明其潜在的生物学和与其他神经发育条件的联系。我们将更具体地了解LI和ASD之间的任何共同遗传责任。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，插入缺失和结构变异），同时捕获全频谱-罕见和常见等位基因。通过增加我们对LI中起作用的基因的理解，我们将更接近能够使用遗传发现作为证据来支持早期干预以改善结果。