Genetics Contributions to Endophenotypes of Dyslexia

描述(由研究人员提供)：我们的目标是识别导致阅读障碍易感性的基因，阅读障碍是一种影响5%-7%学龄儿童的复杂障碍。患有阅读障碍的儿童在学习阅读和拼写方面有意想不到的困难。有充分的证据表明，遗传因素导致了阅读障碍。多个基因座已被牵连，其中一些区域的候选基因目前正在评估中。虽然罕见的家系可能会证明孟德尔式的阅读障碍是由单基因缺陷引起的，但这种疾病的常见形式是遗传复杂的。因此，阅读障碍在表型和遗传上都是异质性的。为了解决表型异质性的问题，我们将单独和根据语言和认知神经科学选择的协变量来研究阅读和写作能力的个体测量以及有助于流利性的过程。美国国立卫生研究院资助的学习障碍中心(UWLDC；1996-2005)经过十年的合作，形成了283个患有诵读困难的多代家庭的数据集。这份特别的资料包括大量与阅读障碍相关的数量表型的数据。NHLBI支持的哺乳动物基因分型服务最近提供了144个家系中1131个个体的基因组扫描数据，进一步丰富了数据集。我们将(I)完成少数优秀个体的招募、表型评估和DMA采样；(Ii)开发表型传播模型，包括执行功能的测量，并在我们的样本中选择最有可能产生良好连锁图谱的模型；(Iii)进行连锁分析，包括全基因组扫描、评估候选多态作为协变量、同时对多条染色体进行联合分析、以及防止假阳性结果的敏感性分析；以及(Iv)对连锁分析中发现的区域进行精细的图谱绘制，以及识别致病基因的初步步骤。在UWLDC任期内完成的分析发现，Chr 2q和13q上的基因影响解码和阅读的速度，从而影响阅读的流畅性，并证实了Chr 15上的一个基因参与了实际单词阅读，从而验证了我们的方法。这项研究将确定阅读障碍的遗传原因，这反过来将导致更早地识别处于危险中的儿童，并针对这种具有终身教育、经济和社会影响的常见残疾进行更有针对性的干预。

DESCRIPTION (provided by investigator): Our goal is to identify genes that confer susceptibility to dyslexia, a complex disorder affecting 5-7 percent of school-age children. Children with dyslexia have unexpected difficulty learning to read and spell. There is ample evidence that genetic factors contribute to dyslexia. Multiple loci have been implicated and candidate genes in some of these regions are now being evaluated. Although rare families may evidence Mendelian forms of dyslexia that result from defects in single genes, the common form of the disorder is genetically complex. Dyslexia is therefore both phenotypically and genetically heterogeneous. To address the issue of phenotypic heterogeneity, we will study individual measures of reading and writing ability and processes contributing to fluency, alone and with covariates chosen on the basis of linguistic and cognitive neuroscience. A ten-year collaborative effort in an NIH-funded Learning Disabilities Center (UWLDC; 1996-2005) resulted in a dataset of 283 multigenerational families with dyslexia. This exceptional resource includes extensive data on a wide range of quantitative phenotypes related to dyslexia. The data set is further enriched by genome scan data recently provided by the NHLBI-supported Mammalian Genotyping Service for 1131 individuals in 144 pedigrees. We will (i) complete recruitment, phenotypic evaluation, and DMA sampling of a small number of outstanding individuals; (ii) develop models of transmission of phenotypes, including measures of executive function, and select those most likely to yield good power for linkage mapping in our sample; (iii) carry out linkage analyses including genomewide scans, evaluation of candidate polymorphisms as covariates, joint analyses of more than one chromosome simultaneously, and sensitivity analyses to guard against false-positive results; and (iv) carry out fine scale mapping of regions identified in the linkage analyses, as well as initial steps towards identifying causative genes. Analyses completed during the tenure of the UWLDC found that genes on chr 2q and 13q affect the speed and therefore fluency of decoding and reading, and corroborated involvement of a gene on chr 15 in real word reading, thus validating our approach. This study will identify genetic causes of dyslexia, which will in turn lead to earlier identification of children at risk and more tailored interventions for this common disability that has life-long educational, economic, and social repercussions.