Genetics Contributions to Endophenotypes of Dyslexia

描述（由研究者提供）：我们的目标是确定基因赋予阅读障碍，一个复杂的疾病影响5- 7%的学龄儿童的易感性。患有诵读困难症的孩子在学习阅读和拼写时会遇到意想不到的困难。有充分的证据表明，遗传因素有助于阅读障碍。多个基因座已经牵连和候选基因在这些地区的一些正在评估。虽然罕见的家庭可能会证明孟德尔形式的阅读障碍，导致单一基因的缺陷，常见的形式的障碍是遗传复杂。因此，诵读困难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，我们将研究个人的阅读和写作能力的措施和过程，有助于流畅性，单独和协变量的基础上选择的语言和认知神经科学。在NIH资助的学习障碍中心（UWLDC; 1996-2005）进行了为期十年的合作努力，获得了283个患有阅读障碍的多代家庭的数据集。这一特殊的资源包括广泛的数据，广泛的数量表型相关的阅读障碍。该数据集进一步丰富的基因组扫描数据最近提供的NHLBI支持的哺乳动物基因分型服务1131个人在144个谱系。我们将（i）完成招募、表型评估和少数杰出个体的DMA采样;（ii）开发表型传播模型，包括执行功能的测量，并选择那些最有可能在我们的样本中产生良好的连锁图谱的模型;（iii）进行连锁分析，包括全基因组扫描，评估作为协变量的候选多态性，同时对一个以上的染色体进行联合分析，并进行敏感性分析，以防止假阳性结果;以及（iv）对连锁分析中确定的区域进行精细绘图，并为确定致病基因采取初步步骤。在UWLDC任职期间完成的分析发现，chr 2 q和13 q上的基因影响解码和阅读的速度和流畅性，并证实了chr 15上的基因参与了真实的的文字阅读，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，这反过来又会导致早期识别有风险的儿童，并为这种具有终身教育，经济和社会影响的常见残疾提供更有针对性的干预措施。

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.