Discovery of the 6p21.3 Reading Disability Gene

6p21.3 阅读障碍基因的发现

• 批准号: 7466283
• 负责人: JEFFREY R GRUEN
• 金额: $ 67.1万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466283
• 关键词: 15q; 6p21.3; 6p22; Achievement; Actins; Admixture; Adult; Affect; Age; Alleles; Behavior; Birth; Bundling; Characteristics; Child; Clinical; Cognitive; Condition; DNA; Databases; Dendrites; Development; Diagnosis; Early Diagnosis; Early Intervention; Early identification; Economics; Enhancers; Environment; Epigenetic Process; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Screening; Genotype; Germany; Goals; Growth; Haplotypes; Heritability; Home environment; Individual; Intelligence; Introns; Italy; Language; Lead; Literacy Programs; Longitudinal Studies; Measures; Medical Records; Modeling; Morbidity - disease rate; Mothers; Neurons; Parents; Pathogenesis; Performance; Population; Population Attributable Risks; Predictive Value; Prevalence; Prevention intervention; Prevention program; Public Health; Range; Reading; Reading Disabilities; Reporting; Resources; Risk; Role; Sampling; Schools; Screening procedure; Students; Testing; Translating; Twin Studies; Work; behavior measurement; cohort; cost; cost effectiveness; demographics; gene environment interaction; genetic association; genetic linkage; gray matter; intervention program; migration; pollutant; prenatal; programs; remediation; size; social; tool

DESCRIPTION (provided by applicant): Reading disability (RD) is characterized by unexpected reading difficulty in children and adults who otherwise have the intelligence and instructional opportunity necessary for accurate and fluent reading. Worldwide, the reported prevalence ranges from 5 to17%. In 1995-96 US schools spent more than $30billion on remediation, mostly for RD. Yet, RD is frequently unrecognized, leading to academic under-achievement with detrimental social and economic consequences. Intervention programs work, but are most effective when RD is diagnosed at an early age. Studies of twins show that the heritability is 44-77%. Four RD genes have emerged from chromosomal loci initially identified by genetic linkage: DYX1C1 (15q), ROBO1 (3q), KIAA0319 (6p22), and DCDC2 (6p22). Evidence for genetic association for KIAA0319 and DCDC2 is particularly strong. The KIAA0319 association has been independently replicated in both the US and the UK, while the DCDC2 association has been independently replicated in the US, Germany, and Italy. All four RD genes have potent effects on neuronal migration. We hypothesize that the risk of RD that is attributable to these specific genes is substantial. To test this hypothesis, we will determine the individual and population attributable risks for RD conferred by all single or combinations of alleles from these genes in a sample of 10,233 randomly selected children from the Avon Longitudinal Study of Parents and Children (ALSPAC). To determine the non-genetic factors that contribute to RD, we will first model the effects of school, home and individual characteristics and their interactions on a variety of cognitive, academic, and behavioral measures at different ages in order to identify significant covariates for genetic studies. To determine the risk of RD attributable to these genes, we will genotype all the known RD-alleles in the ALSPAC, including KIAA0319, DCDC2, intervening 6p22 markers, BV677278 alleles, ROBO1, and DYX1C1. We will then test for association with single alleles and reconstructed haplotypes conditioned by the covariate modeling in AIM 1, define the attributable risks of RD for any child and for the population associated with any single RD-allele and with all combinations of alleles. We will also assess gene-gene and gene-environment interactions, and epigenetic effects. Finally, to validate these results, we will attempt to replicate our positive findings in a random, sub- sample of 700 ALSPAC trios, in which we will correct for population admixture as well as assess parent-of- origin effects that can arise by epigenetic effects. We expect these studies will confirm and quantify the substantial risk of RD conferred by these genes which should stimulate further studies to lay the groundwork for implementing genetic screening programs for RD. Such screening programs could lead to early identification of those at increased risk, as well as to early interventions for those that are affected, thereby decreasing the considerable morbidity caused by RD. PUBLIC HEALTH RELEVANCE: The goal of these studies is to determine the risk of reading disability attributable to any single or combination of previously described reading disability genes. These studies are a crucial first step towards subsequent studies to try to translate these advances in our understanding of the genetics of reading disability to actual practical uses in populations, such as screening. An accurate and cost-effective population screening tool for reading disability would be useful for early detection of children at risk who would benefit from prevention programs, for resource planning by school districts, for detecting older children who are struggling in school in whom the diagnosis may have been missed or misdiagnosed, for adult literacy programs, and for tailoring prevention and intervention programs to specific students.

描述（由申请人提供）：阅读障碍（RD）的特征是儿童和成年人的意外阅读困难，否则他们就具有准确和流利的阅读所需的智力和教学机会。在全球范围内，据报道的患病率从5％到17％不等。在1995 - 96年，美国学校花费了超过300亿美元的补救措施，主要用于RD。然而，RD经常无法认可，从而导致学术成就不足，而有害的社会和经济后果。干预计划有效，但在诊断出RD时最有效。对双胞胎的研究表明，遗传力为44-77％。最初通过遗传连接鉴定的染色体基因座出现了四个RD基因：DYX1C1（15Q），ROBO1（3Q），KIAA0319（6P22）和DCDC2（6P22）。 KIAA0319和DCDC2遗传关联的证据特别有力。 KIAA0319协会在美国和英国都独立复制，而DCDC2协会在美国，德国和意大利进行了独立复制。所有四个RD基因对神经元迁移均具有有效的影响。我们假设归因于这些特定基因的RD风险是很大的。为了检验这一假设，我们将确定来自这些基因等位基因的所有单一或组合的RD的个体和人群风险，其中10,233名来自父母和子女的Avon纵向研究的10,233个随机选择的儿童（ALSPAC）。为了确定导致RD的非遗传因素，我们将首先对学校，家庭和个人特征的影响进行建模，及其对不同年龄段的多种认知，学术和行为措施的相互作用，以确定遗传研究的重要协变量。为了确定归因于这些基因的RD风险，我们将基因型ALSPAC中所有已知的RD-learter，包括KIAA0319，DCDC2，介入6p22标记，BV677278等位基因，Robo1和Dyx1c1。然后，我们将测试与AIM 1中协变量建模有关的单个等位基因和重建的单倍型的关联，定义任何儿童的RD的可归因风险以及与任何单个RD-Allele相关的人群以及与所有等位基因组合相关的人群。我们还将评估基因基因和基因环境相互作用以及表观遗传效应。最后，为了验证这些结果，我们将尝试以700个ALSPAC三重奏的随机样本来复制我们的积极发现，其中我们将纠正种群混合物，并评估可能通过表观遗传效应而产生的父母效应。我们预计这些研究将确认并量化这些基因赋予的RD的实质性风险，这些风险应刺激进一步的研究，以为实施RD实施基因筛查计划奠定基础。这样的筛查计划可能会导致对风险增加的人的早期识别，以及对受影响者的早期干预措施，从而降低了RD引起的大量发病率。公共卫生相关性：这些研究的目的是确定可归因于先前描述的阅读障碍基因的任何单一或组合的阅读障碍的风险。这些研究是朝着随后的研究迈出的至关重要的第一步，试图将这些进步转化为我们对阅读障碍的遗传学的理解，例如筛查等人群中的实际实际用途。用于阅读障碍的准确且具有成本效益的人口筛查工具将有助于早期发现有风险的儿童，这些儿童将受益于预防计划，用于学区的资源计划，用于检测在学校中挣扎的年龄较大的儿童，这些孩子可能会错过或误导诊断，以识别或误诊，用于成人识字计划，以及针对特定学生的预防和干预计划。