Sequencing of significant signals from cleft lip GWAS

唇裂 GWAS 重要信号的测序

• 批准号: 8006904
• 负责人: JEFFREY C MURRAY
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006904
• 关键词: 8q24; Affect; Behavior Therapy; Birth; Cessation of life; Cleaved cell; Cleft Lip; Clinical; Cognitive; Collaborations; Collection; Communities; Complex; Congenital Abnormality; Coupled; Data; Data Analyses; Dental; Detection; Economic Burden; Etiology; Family; Fishes; Genes; Genetic; Individual; Leadership; Life; Malignant Neoplasms; Mental disorders; Mus; Mutation; Nutritional; Operative Surgical Procedures; Palate; Parents; Persons; Phenotype; Publishing; Risk; Sampling; Sequence Analysis; Signal Transduction; Speech; Testing; Variant; Work; cleft lip and palate; comparative; craniofacial; genome wide association study; genome-wide; innovation; novel; success; trait; transmission process

DESCRIPTION (provided by applicant): Clefts of the lip and/or palate (CLP) are common birth defects of complex etiology. About 70% of individuals are born with an isolated cleft and no other structural or cognitive abnormalities. Clefts affect 1 in 700 births and require surgical, nutritional, dental, speech, and behavioral interventions. They impose substantial economic burdens with an expense per person in excess of $200,000 lifetime. In addition to their impact in early life, CLP is associated with a lifetime increase in death from all causes as well as an increased risk for mental health disorders and cancer. It is now practical to identify common variants associated with the etiology of complex traits by using a combination of family collections, careful phenotyping, and genome wide associations studies (GWAS). The next critical step of moving from association to specific causal variant identification has been difficult although there is one success in CLP studies. This next step will be greatly facilitated by deep sequence analysis of the associated regions with subsequent confirmation by expression and functional analysis. We will use a large (1900 case/parent trios) recently completed GWAS coupled to samples and data from 3 smaller, published GWAS studies to select regions for deep sequencing. Four well replicated loci/genes will form the core of this effort (IRF6, MAFB, ABCA4 and 8q24) with two other genes (VAX1 and F0XE1) selected that have compelling supportive data as well. A strong team has been assembled to carry out the work and the project has many novel and innovative features including: parental samples available on 3500 cases enabling use of the transmission disequilibrium test for analysis and the detection of de novo rare variants; a confirmed etiologic variant in IRF6 that provides a "control"; close collaborations that allow for expression analysis to be used in both region selection and mutation verification; collaborations to provide functional replication in mouse and fish; the Co-I's leadership of the FaceBase consortium that will provide for rapid dissemination of data and results to the craniofacial community. We believe this project can contribute to an overall better understanding of how to use sequence data to find causal variants and to the causes of CLP. RELEVANCE: Conversion of genome-wide (GWAS) association signals to finding specific mutations is critical to genetic findings into clinical utility. This project will take advantage of a very large GWAS on cleft lip and palate that includes parental samples that provide unique opportunities for detection of causal mutations for this important birth defect. It will provide opportunities for comparative data analysis that will be useful to other studies undergoing similar approaches.

描述（由申请人提供）：唇裂和/或腭裂（CLP）是常见的先天性缺陷，病因复杂。大约70%的人出生时患有孤立性唇裂，没有其他结构或认知异常。每700名新生儿中就有1人患有唇裂，需要手术、营养、牙科、语言和行为干预。它们造成了巨大的经济负担，每人一生的费用超过20万美元。除了对生命早期的影响外，CLP还与一生中各种原因导致的死亡增加以及精神健康障碍和癌症的风险增加有关。现在，通过结合家族收集、仔细的表型分析和全基因组关联研究（GWAS），确定与复杂性状病因学相关的常见变异是可行的。虽然在CLP研究中有一个成功，但从关联到特定因果变异识别的下一个关键步骤是困难的。相关区域的深度序列分析以及随后的表达和功能分析将极大地促进下一步的研究。我们将使用最近完成的大型（1900例/父母三人组）GWAS与来自3个较小的已发表的GWAS研究的样本和数据相结合，以选择区域进行深度测序。四个复制良好的位点/基因将构成这项工作的核心（IRF6， MAFB， ABCA4和8q24），另外两个选择的基因（VAX1和F0XE1）也有令人信服的支持数据。已经组建了一个强大的团队来开展这项工作，该项目具有许多新颖和创新的特点，包括：在3500个病例中提供亲代样本，可以使用传播不平衡测试进行分析和检测新生罕见变异；提供“对照”的IRF6的确诊病因变异；密切合作，允许表达分析用于区域选择和突变验证；在小鼠和鱼类中提供功能复制的合作；该组织领导的FaceBase联盟将为颅面医学社区提供快速传播数据和结果。我们相信这个项目可以有助于更好地理解如何使用序列数据来找到因果变异和CLP的原因。