Discovery of the 6p21.3 Reading Disability Gene

6p21.3 阅读障碍基因的发现

• 批准号: 7565982
• 负责人: JEFFREY R GRUEN
• 金额: $ 65.79万
• 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/7565982
• 关键词: 15q; 6p21.3; 6p22; Achievement; Actins; Admixture; Adult; Affect; Age; Alleles; Behavior; Birth; Bundling; Characteristics; Child; Clinical; Cognitive; DNA; Databases; Dendrites; Development; Diagnosis; Early Diagnosis; Early identification; Early treatment; 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 program; Preventive Intervention; 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; non-genetic; pollutant; prenatal; programs; public health relevance; remediation; 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）的特征是儿童和成人出现意想不到的阅读困难，否则他们就有准确和流利阅读所必需的智力和教学机会。在世界范围内，报告的患病率为5%至17%。1995年至1996年，美国学校在补习上花费了300多亿美元，其中大部分用于研发。然而，研发常常得不到认可，导致学业成绩不佳，造成有害的社会和经济后果。干预计划是有效的，但当RD在早期被诊断出来时是最有效的。对双胞胎的研究表明，遗传率为44-77%。四个RD基因从最初通过遗传连锁鉴定的染色体位点中出现：DYX1C1 (15q), ROBO1 (3q), KIAA0319 （6p22）和DCDC2 （6p22）。KIAA0319和DCDC2基因关联的证据尤其充分。KIAA0319协会已在美国和英国独立复制，而DCDC2协会已在美国、德国和意大利独立复制。所有四种RD基因都对神经元迁移有强有力的影响。我们假设，RD的风险可归因于这些特定基因是实质性的。为了验证这一假设，我们将从雅芳父母与儿童纵向研究（ALSPAC）中随机抽取10,233名儿童样本，确定这些基因的所有单个或组合等位基因赋予RD的个体和群体归因风险。为了确定导致RD的非遗传因素，我们将首先模拟学校、家庭和个人特征及其相互作用对不同年龄的各种认知、学术和行为测量的影响，以确定遗传研究的重要协变量。为了确定这些基因导致RD的风险，我们将对ALSPAC中所有已知的RD等位基因进行基因分型，包括KIAA0319、DCDC2、干预6p22标记、BV677278等位基因、ROBO1和DYX1C1。然后，我们将测试与单等位基因的关联，并通过AIM 1中的协变量建模来重建单倍型，定义任何儿童、任何单一RD等位基因相关人群和所有等位基因组合的RD归因风险。我们还将评估基因-基因和基因-环境的相互作用，以及表观遗传效应。最后，为了验证这些结果，我们将尝试在700个ALSPAC三胞胎的随机子样本中复制我们的积极发现，其中我们将校正种群混合以及评估可能由表观遗传效应引起的亲本起源效应。我们希望这些研究能够确认和量化这些基因所带来的RD的重大风险，从而刺激进一步的研究，为RD的遗传筛查项目奠定基础。这些筛查项目可以早期识别风险增加的人群，并对受影响的人群进行早期干预，从而降低RD引起的相当大的发病率。这些研究的目的是确定阅读障碍的风险归因于任何单一或组合先前描述的阅读障碍基因。这些研究是后续研究的关键第一步，这些研究试图将我们对阅读障碍遗传学的理解中的这些进展转化为人群中的实际应用，例如筛查。一种准确且具有成本效益的阅读障碍人群筛查工具将有助于早期发现有风险的儿童，这些儿童将从预防项目中受益，有助于学区的资源规划，有助于发现在学校挣扎的年龄较大的儿童，这些儿童可能被遗漏或误诊，有助于成人扫盲项目，有助于针对特定学生制定预防和干预项目。