Molecular Genetics of Language and Related Cognition in Families

描述(由申请者提供)：定量遗传学研究一直表明，特定语言障碍(SLI)是可遗传的组成部分。然而，只有少数几个组织已经开始评估SLI的遗传流行病学。在我们正在进行的研究的前一阶段，我们发现了令人信服的证据，证明了13q21-22内存在风险多态，并随后进行了复制。然而，在13q21区域内增加SLI风险的特定易感等位基因尚未确定。同样重要的是，以前的研究没有在可能导致SLI的多个、数量分布的潜在语言过程的背景下检查SLI的遗传病因学或病因。因此，系统性红斑狼疮患者的大量临床异质性和伴随的遗传异质性之间的关系在很大程度上仍未被探索。因此，本应用程序的目标是解决三个具体目标。我们建议应用多水平方法的组合来定位SLI易感等位基因。我们将使用生物信息学和分子方法来识别13q21内可能存在的易感等位基因序列(目标1)。我们将扩大我们的家族收集，以增加检测新的SLI基因座和SLI相关QTL的能力(目标2)。我们将采用新的多变量方法，预计将更好地改进我们的本地化，增加能力，并允许我们在SLI文献(目标3)中几个潜在语言过程的多变量上下文中检查这些基因座。这些目标很重要，因为它们将基因分析与可能导致SLI的多种认知途径联系起来，希望能更好地识别和治疗。 公共卫生相关性：特殊语言障碍是一种常见的障碍；大约5%-7%的学龄儿童符合特殊语言障碍的标准，这些儿童总体上代表了全国公立学校系统中接受特殊教育服务的学生的最大比例。了解各种遗传风险因素和对语言发育的负面影响可能会导致更早的识别和更早的治疗，也可能有助于基于潜在的神经生物学开发新的治疗方法。

DESCRIPTION (provided by applicant): Quantitative genetic studies have consistently demonstrated a heritable component for specific language impairment (SLI). However, only a handful of groups have begun assessing the genetic epidemiology of SLI. In a previous phase of our ongoing research, we found compelling evidence for a risk polymorphism within 13q21-22, which was subsequently replicated. However, the specific susceptibility allele that acts to increase risk for SLI within 13q21 region has not yet been identified. Equally important, previous studies have not examined the genetic etiology or etiologies of SLI in the context of the multiple, quantitatively distributed underlying language processes that may lead to SLI. Thus, the relationship between the substantial clinical heterogeneity among individuals with SLI and concomitant genetic heterogeneity remains largely unexplored. The goal of this application, therefore, is to address three specific aims. We proposed to localize SLI susceptibility alleles by applying a combination of multi-level approaches. We will use bioinformatics and molecular approaches to identify possible susceptibility-allele-harboring sequences within 13q21 (Aim 1). We will extend our family collection to increase power to detect novel SLI loci and SLI-related QTLs (Aim 2). We will employ new multivariate approaches which are expected to better refine our localization, increase power, and allow us to examine these loci in the multivariate context of several underlying language processes from the SLI literature (Aim 3). These aims are important because they link genetic analysis with the multiple cognitive pathways that may lead to SLI in the hopes of better identification and treatment. PUBLIC HEALTH RELEVANCE: Specific language impairment is a common disorder; approximately 5-7 percent of school age children meet criteria for specific language impairment and collectively these children represent the largest portion of pupils receiving special education services within the nation's public school system. Understanding the variety of genetic risk factors and negatively influences language development may lead to earlier identification and hence earlier treatment, and may also help in the development of new therapeutic approaches based on the underlying neurobiology.