MOLECULAR GENETIC AND BEHAVIORAL STUDIES OF PROFOUNDLY IMPARIED READING

在这一应用中，我们建议研究严重阅读障碍的行为特征和遗传学基础。 具体地说，我们将建立一个独特的样本，包括500名严重受影响的小学儿童 通过PMRN数据库查明，然后将招募至少两名一级亲属 先证者的样本约为1500人。我们将进行全面的行为评估，以 所有小学生，并收集所有参与者的DNA样本。行为表型将 要从横向和纵向两方面进行全面研究。此外，我们建议进行一项 对特定阅读障碍(SRD)进行相对狭隘但深入的分子遗传学研究。 具体地说，我们的目标是在新收集的PMRN数据库样本中评估 特定的候选基因和SRD。我们建议从目前正在研究的一种基因开始这项工作， KIAA0319，并预计在该项目的生命周期内还会有其他候选基因被提出 通过世界各地不同研究小组的努力。在调查这些关联时，我们 建议明确一种数据分析方法，允许同时分析多变量 表型和多个QTL的横截面和纵向。此外，虽然相对较小， 在大小上，这项研究将为每个候选基因的贡献提供一个独特的前景 考虑全球遗传中已识别的风险和/或保护性等位基因以及风险和/或保护性单倍型 变异和进化的背景。具体地说，候选基因将被调查祖先的等位基因。 来自38个世界的样本中的单倍型和等位基因和单倍型频率的全球变异 种群和一些灵长类物种。这种深入的分析将允许对频率进行评估 和结构的候选基因的单倍型，因此，将增加 表示关联存在的结果的概括性。总而言之，我们建议将 行为分析和统计、分子和群体遗传学，试图理解 一种独特的、表型的SRD的特定候选基因与多个方面的关联 通过先证者确定的一级亲属三人的大样本，其严重程度 阅读障碍使他们在单字处理指标上的表现低于第三个百分位数。

In this application, we propose to study behavioral profiles and genetic bases of severe reading impairment. Specifically, we will establish a unique sample of 500 severely affected elementary schools children ascertained through the PMRN database and will then recruit at least two first-degree relatives of the probands for a sample of ~1,500 individuals. We will administer a comprehensive behavioral assessment to all elementary school children and collect DNA samples from all participants. The behavioral phenotypes will be comprehensively studied, both cross-sectionally and longitudinally. In addition, we propose to conduct a relatively narrowly targeted, but in-depth, molecular-genetic study of Specific Reading Disability (SRD). Specifically, we aim to evaluate, in the newly collected PMRN database samples, the association between specific candidate genes and SRD. We propose to begin this work with a gene currently under examination, KIAA0319, and anticipate that during the life of this project there will be other candidate genes put forward through the efforts of different research groups around the world. In investigating these associations, we propose to crystallize a data-analytic approach that permits simultaneous analyses of multivariate phenotypes and multiple QTLs both cross-sectionally and longitudinally. In addition, although relatively small in magnitude, this study will offer a unique prospective on the contribution of each of the candidate genes by considering identified risk and/or protective alleles and risk and/or protective haplotypes in global genetic variation and evolutionary contexts. Specifically, the candidate genes will be investigated for ancestral alleles and haplotypes and global variation of allele and haplotype frequencies in samples from 38 world populations and a number of primate species. This in-depth analysis will permit evaluation of the frequency and structure of the candidate genes' haplotype around the world and, therefore, will increase the generalizability of results indicating the presence of association. In summary, we propose to combine behavior analyses and statistical, molecular, and population genetics in an attempt to understand associations between specific candidate genes and multiple facets of SRD in a unique, phenotypically informative, large sample of trios of first-degree relatives ascertained through probands whose severity of reading impairment puts their performance below the 3rd percentile on indicators of single-word processing.