Genetics Contributions to Endophenotypes of Dyslexia

遗传学对阅读障碍内表型的贡献

• 批准号: 7635898
• 负责人: WENDY H RASKIND
• 金额: $ 36.55万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635898
• 关键词: 13q; Abbreviations; Achievement; Address; Adult; Affect; Alzheimer' s Disease; Attention; Candidate Disease Gene; Child; Chromosome Mapping; Chromosomes; Code; Collection; Color; Complex; DRD4 gene; DSM-IV; Data; Data Analyses; Data Set; Databases; Defect; Diagnosis; Digit structure; Disease; Dyslexia; Early identification; Economics; Evaluation; Family; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome Scan; Genotype; Goals; Gray unit of radiation dose; Heterogeneity; Human Herpesvirus 4; Individual; Intelligence; Intervention; Joints; Knowledge; Language; Lead; Learning; Learning Disabilities; Letters; Life; Linguistics; Link; Linkage Disequilibrium; Location; Lymphocyte; Maps; Markov Chains; Measures; Memory; Minisatellite Repeats; Modeling; Molecular; National Heart, Lung, and Blood Institute; Oral; Orthography; Pathway interactions; Pattern; Phenotype; Polymerase Chain Reaction; Predisposition; Process; Process Assessment; Quality Control; Quantitative Trait Loci; Reading; Recurrence; Research; Research Personnel; Resources; Restriction fragment length polymorphism; Risk; Sampling; School-Age Population; Services; Short Tandem Repeat Polymorphism; Single Nucleotide Polymorphism; Speed; System; Testing; Universities; Upper arm; Vision; Washington; Writing; base; cognitive neuroscience; cohort; disability; dopamine D4 receptor; endophenotype; executive function; genetic linkage analysis; genetic pedigree; genome wide association study; genome-wide; improved; member; mind control; phonology; segregation; social; spelling; trait; transmission process

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.

描述（调查员提供）：我们的目标是确定给予阅读障碍易感性的基因，这是一种复杂的疾病，影响了5-7％的学龄儿童。阅读障碍儿童学习阅读和拼写有意外的困难。有足够的证据表明遗传因素导致阅读障碍。已经牵涉到多个基因座，其中一些区域中的候选基因正在评估。尽管罕见的家族可能证明了由单个基因缺陷导致的孟德尔形式的阅读障碍，但该疾病的常见形式在遗传上是复杂的。因此，阅读障碍既是表型和遗传异质性的。为了解决表型异质性的问题，我们将研究单独的阅读和写作能力和过程的单独措施，并根据语言和认知神经科学选择促成流利度。在NIH资助的学习障碍中心（UWLDC; 1996-2005）进行了十年的合作努力，导致了283个多代家庭阅读障碍的数据集。这种特殊资源包括有关与阅读障碍有关的广泛定量表型的广泛数据。该数据集由NHLBI支持的哺乳动物基因分型服务最近提供的基因组扫描数据进一步丰富，该数据为144个谱系中的1131个个体提供了基因分型服务。我们将（i）（i）少数杰出个人的完整招聘，表型评估和DMA采样； （ii）开发表型传输模型，包括执行功能的度量，并选择最有可能在样本中链接映射的良好功率的模型； （iii）进行连锁分析，包括全基因组扫描，评估候选多态性作为协变量，同时同时进行多个染色体的联合分析以及敏感性分析以防止假阳性结果； （iv）对链接分析中确定的区域以及识别因果基因的初步步骤进行精细规模映射。在UWLDC任职期间完成的分析发现，CHR 2Q和13Q上的基因会影响解码和阅读的速度，因此流利，并在真实单词阅读中对Chr 15对Chr 15的介绍，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，这反过来又导致对处于危险的儿童和更量身定制的干预措施，以实现终身教育，经济和社会影响。