Molecular Genetics of Language and Related Cognition in Families

描述（由申请人提供）：定量基因研究一致证明了特定语言障碍（SLI）的遗传成分。然而，只有少数小组开始评估特殊语言障碍的遗传流行病学。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13q21-22存在风险多态性，随后又进行了重复研究。然而，13q21区域中增加SLI风险的特定易感等位基因尚未被确定。同样重要的是，以前的研究没有在可能导致特殊语言障碍的多种、定量分布的潜在语言过程的背景下检查特殊语言障碍的遗传病因或病因。因此，SLI个体之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，这个应用程序的目标是解决三个特定的目标。我们提出了结合多层次的方法来定位SLI易感等位基因。我们将使用生物信息学和分子方法来鉴定13q21中可能的易感等位基因窝藏序列（目的1）。我们将扩展我们的家族收集，以提高检测新的SLI位点和SLI相关qtl的能力（目标2）。我们将采用新的多变量方法，这些方法有望更好地改进我们的定位，增加能力，并允许我们在SLI文献中几种潜在语言过程的多变量背景下检查这些基因座（目标3）。这些目标很重要，因为它们将基因分析与可能导致特殊语言障碍的多种认知途径联系起来，以期更好地识别和治疗。

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.