Genetics Contributions to Endophenotypes of Dyslexia

遗传学对阅读障碍内表型的影响

• 批准号: 7318728
• 负责人: WENDY H RASKIND
• 金额: $ 35.16万
• 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/7318728
• 关键词: 13q; 9 alpha,11 alpha,15 alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trienoic acid; 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; Genome Scan; Genotype; Goals; Heterogeneity; Human Herpesvirus 4; Individual; Intelligence; Intervention; Joints; Knowledge; Language; Lead; Learning; Learning Disabilities; Letters; Life; Linguistics; Link; Linkage Disequilibrium; Location; Maps; Markov Chains; Measures; Memory; Minisatellite Repeats; Modeling; Molecular; Numbers; O,O-diisopropyl-S-benzylthiophosphate; OSA; Orthography; Pathway interactions; Pattern; Phenotype; Polymerase Chain Reaction; Predisposition; Process; Process Assessment; Quality Control; Quantitative Trait Loci; Range; Reading; Recurrence; Research; Research Personnel; Resources; Restriction fragment length polymorphism; Risk; Sampling; School-Age Population; Services; Short Tandem Repeat Polymorphism; Single Nucleotide Polymorphism; Speed; Standards of Weights and Measures; 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; improved; member; mind control; phonology; phosphoric diester hydrolase; programs; 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（由研究者提供）：我们的目标是确定导致阅读障碍易感性的基因，阅读障碍是一种影响 5-7% 学龄儿童的复杂疾病。患有阅读障碍的儿童在学习阅读和拼写方面会遇到意想不到的困难。有充分的证据表明遗传因素会导致阅读障碍。涉及多个基因座，目前正在评估其中一些区域的候选基因。尽管罕见的家庭可能会出现由单基因缺陷引起的孟德尔形式的阅读障碍，但这种疾病的常见形式在遗传上是复杂的。因此，阅读障碍在表型和遗传上都是异质的。为了解决表型异质性问题，我们将研究阅读和写作能力的个体测量以及有助于流畅性的过程，单独和基于语言和认知神经科学选择的协变量。 NIH 资助的学习障碍中心（UWLDC；1996-2005）经过十年的合作，得出了包含 283 个患有阅读障碍的多代家庭的数据集。这一特殊资源包括与阅读障碍相关的各种定量表型的大量数据。 NHLBI 支持的哺乳动物基因分型服务最近为 144 个谱系的 1131 个个体提供了基因组扫描数据，进一步丰富了该数据集。我们将（i）完成少数优秀个体的招募、表型评估和DMA采样； (ii) 开发表型传递模型，包括执行功能的测量，并选择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、作为协变量的候选多态性评估、同时对多个染色体进行联合分析以及敏感性分析以防止假阳性结果； (iv) 对连锁分析中确定的区域进行精细尺度绘图，以及确定致病基因的初步步骤。在 UWLDC 任职期间完成的分析发现，2q 和 13q 上的基因影响解码和阅读的速度，从而影响解码和阅读的流畅性，并证实了 15 号基因在实际单词阅读中的参与，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，从而更早地识别处于危险中的儿童，并针对这种具有终生教育、经济和社会影响的常见残疾采取更有针对性的干预措施。