Discovery of the 6p.21.3 Reading Disability Gene

6p.21.3 阅读障碍基因的发现

• 批准号: 6881673
• 负责人: JEFFREY R GRUEN
• 金额: $ 55.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881673
• 关键词: behavioral /social science research tag; chromosomes; clinical research; functional magnetic resonance imaging; genetic polymorphism; genetic susceptibility; genotype; human subject; linkage disequilibriums; matrix assisted laser desorption ionization; neural information processing; neuropsychological tests; nucleic acid sequence; phenotype; quantitative trait loci; reading; reading disorder; statistics /biometry

DESCRIPTION (provided by applicant): Reading disability (RD) is a multifactorial heritable disorder defined as difficulty in learning to read despite adequate intelligence and opportunity. It is the most common neurobehavioral disorder affecting children, with a prevalence rate of 10 to 20% accounting for more than 80% of all learning disabilities. While acquisition of skilled reading is to a great extent influenced by important environmental factors such as exposure to print media, story reading, and early childhood education, our group and others have shown that approximately 50% or more of the deficits in RD children can be attributed to inherited factors. Specific risk factors that make a child susceptible to RD are variant alleles of a small number of genes at loci yet to be precisely identified on human chromosome 18, 25, 6, 3, 2, and 2. Clues to the function of these genes may be found in the converging data from functional magnetic resonance imaging (fMRI) studies, which consistently and convincingly show that the normal neural circuitry activated in reading is disrupted in children and adults with RD. We recently confined the location of the strongest-acting of the RD susceptibility loci to a 4 million base region on chromosome 6p through high-resolution studies of linkage disequilibrium in families whose children have RD. Thus, we hypothesize that the 6pRD gene can be identified by an intense genetic analysis of this region using a high-density marker panel in well-characterized cohorts. To address this hypothesis we will: A) Define three RD cohorts for analysis, B) Map the peak of linkage disequilibrium to localize the 6pRD gene, and C) Identify sequence variants in gene-candidates. These studies will take advantage of our experience in gene mapping of the 6p region and our experience in characterizing RD. We anticipate that these studies will lead to the identification of a gene that plays a role in the pathogenesis of RD.

描述（由申请人提供）：阅读障碍（RD）是一种多因素遗传性疾病，定义为尽管有足够的智力和机会，但仍难以学习阅读。它是影响儿童的最常见的神经行为障碍，患病率为10%至20%，占所有学习障碍的80%以上。虽然熟练阅读能力的获得在很大程度上受到重要环境因素的影响，如接触印刷媒体、故事阅读和幼儿教育，但我们的研究小组和其他研究人员已经表明，RD儿童中约50%或更多的缺陷可归因于遗传因素。使儿童易患RD的特定风险因素是人类染色体18、25、6、3、2和2上尚未精确鉴定的基因座上少数基因的变异等位基因。这些基因功能的线索可以在功能性磁共振成像（fMRI）研究的汇聚数据中找到，这些研究一致且令人信服地表明，患有RD的儿童和成人在阅读中激活的正常神经回路受到干扰。最近，我们通过高分辨率的连锁不平衡研究，在其子女有RD的家庭中，将RD易感基因座的最强作用的位置限制在染色体6p上的400万个碱基区域。因此，我们假设6pRD基因可以通过在特征明确的队列中使用高密度标记物组对该区域进行密集的遗传分析来鉴定。为了解决这一假设，我们将：A）定义三个RD群组用于分析，B）绘制连锁不平衡的峰值以定位6pRD基因，以及C）鉴定基因候选物中的序列变体。这些研究将利用我们在6p区域基因定位方面的经验和我们在表征RD方面的经验。我们预计，这些研究将导致识别在RD发病机制中发挥作用的基因。