Discovery of the 6p21.3 Reading Disability Gene

6p21.3 阅读障碍基因的发现

基本信息

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
项目类别：
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

项目摘要

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）的特点是儿童和成人出现意外的阅读困难，而他们原本拥有准确和流利阅读所需的智力和指导机会。在世界范围内，报告的患病率范围为 5% 至 17%。 1995-96 年，美国学校在补救上花费了超过 300 亿美元，其中大部分用于 RD。然而，研发经常不被认识，导致学术成绩不佳，造成有害的社会和经济后果。干预计划是有效的，但只有在早期诊断出 RD 时才最有效。对双胞胎的研究表明遗传率为44-77%。从最初通过遗传连锁鉴定的染色体位点中出现了四个 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。所有四个 RD 基因都对神经元迁移产生有效影响。我们假设这些特定基因导致的 RD 风险很大。为了检验这一假设，我们将从雅芳父母和儿童纵向研究 (ALSPAC) 中随机选择的 10,233 名儿童样本中，确定这些基因的所有单个或等位基因组合所赋予的个体和群体 RD 风险。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及其相互作用对不同年龄的各种认知、学业和行为测量的相互作用进行建模，以便识别遗传的显着协变量。研究。为了确定这些基因引起的 RD 风险，我们将对 ASPAC 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，我们将测试与单个等位基因和由 AIM 1 中的协变量模型调节的重建单倍型的关联，定义任何儿童以及与任何单个 RD 等位基因和所有等位基因组合相关的人群的 RD 归因风险。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，我们将尝试在 700 个 ASPAC 三人组的随机子样本中复制我们的积极发现，其中我们将校正群体混合并评估表观遗传可能产生的亲本效应影响。我们预计这些研究将确认并量化这些基因赋予 RD 的重大风险，这将刺激进一步的研究，为实施 RD 基因筛查计划奠定基础。此类筛查计划可以尽早识别高风险人群，并对受影响的人群进行早期干预，从而降低 RD 引起的高发病率。公共健康相关性：这些研究的目的是确定由先前描述的阅读障碍基因中的任何单个或组合导致的阅读障碍风险。这些研究是后续研究的关键第一步，旨在将我们对阅读障碍遗传学的理解的进展转化为人群的实际应用，例如筛查。一个准确且具有成本效益的阅读障碍人群筛查工具将有助于及早发现处于危险中的儿童，这些儿童将从预防计划中受益，有助于学区的资源规划，有助于发现在学校遇到困难的年龄较大的儿童，这些儿童的诊断可能会使其受益。对于成人扫盲计划以及针对特定学生量身定制的预防和干预计划，这些问题都被遗漏或误诊。