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：口语是人类行为的近乎普遍的特征，它将个人束缚在社会群体中，并在他们的照顾者（LI）的情况下很少有意识地互动，学习，解决问题和商业。造成这种社会问题的一个贡献者是一种神经发育的内容。一个大量的绅士组成部分，但是过去十年中使用的技术涉及一些特定的基因，我们建议使用整个基因组性别，从而产生最多的综合性目录，以造成语言受损的遗传变异和语言损害的个人（AIM 1）使用此目录，我们将使用计算方法对每个遗传变体的最可能的功能影响。 2）用于富集Casses的功能变化（语言受损）与控制（语言验证）。语言相关的转录因子FOXP2与某些人的自闭症谱系障碍（ASDS）相关在ASD变体上的LI遗传变异中，这种分析将使这些条件之间的关系泛滥对所有遗传变异模式的综合分析（单个核苷酸变体，indels变体）对任何共享的LI和ASD的更具体理解。结果。