Molecular Genetics of Language and Related Cognition in Families

描述（由申请人提供）：定量遗传学研究一直证明了特定语言障碍（SLI）的遗传成分。然而，只有少数研究小组开始评估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13 q21 -22内的风险多态性的令人信服的证据，随后被复制。然而，在13 q21区域内增加SLI风险的特异性易感等位基因尚未确定。同样重要的是，以前的研究没有检查的遗传病因学或病因学的背景下，多个，定量分布的潜在的语言过程，可能会导致SLI。因此，SLI个体间的临床异质性与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，本申请的目的是解决三个具体目标。我们建议通过应用多层次方法的组合来定位SLI易感性等位基因。我们将使用生物信息学和分子方法来确定可能的易感性等位基因窝藏序列在13 q21（目标1）。我们将扩大我们的家庭收集，以增加功率检测新的SLI位点和SLI相关的QTL（目标2）。我们将采用新的多元方法，预计将更好地完善我们的本地化，增加功率，并允许我们检查这些位点的多变量背景下的几个潜在的语言过程从SLI文献（目标3）。这些目标很重要，因为它们将遗传分析与可能导致SLI的多种认知途径联系起来，以期更好地识别和治疗。 公共卫生相关性：特殊语言障碍是一种常见的疾病;大约5%-7%的学龄儿童符合特殊语言障碍的标准，这些儿童在全国公立学校系统接受特殊教育服务的学生中占最大比例。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早期识别，从而早期治疗，也可能有助于开发基于潜在神经生物学的新治疗方法。

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.