Sequencing of significant signals from cleft lip GWAS

描述(申请人提供)：唇腭裂(CLP)是常见的复杂病因的出生缺陷。大约70%的人出生时就患有孤立的唇裂，没有其他结构或认知异常。每700名新生儿中就有一名患有唇裂，需要手术、营养、牙科、言语和行为干预。它们造成了巨大的经济负担，每人一生的支出超过20万美元。除了对早期生活的影响外，CLP还与各种原因导致的终生死亡增加以及精神健康障碍和癌症风险的增加有关。现在，通过结合使用家系收集、仔细的表型鉴定和基因组广泛关联研究(GWAS)来识别与复杂性状的病因相关的常见变异是可行的。从关联转移到特定因果变异识别的下一个关键步骤一直是困难的，尽管在CLP研究中已经取得了一项成功。对相关区域进行深度序列分析，并随后通过表达和功能分析进行确认，将极大地促进这一下一步。我们将使用最近完成的一个大的(1900个病例/亲代三个)GWAS结合来自3个较小的已发表的GWAS研究的样本和数据来选择要进行深度测序的区域。四个复制良好的基因座/基因将构成这项工作的核心(IRF6、MAFB、ABCA4和8q24)，另外两个基因(VAX1和F0XE1)也将被选中，它们也具有令人信服的支持数据。已经组建了一支强大的团队来开展这项工作，该项目有许多新颖和创新的特点，包括：可用于3500例病例的父母样本，能够利用传递不平衡测试进行分析和检测新的罕见变异；IRF6中确认的病原学变异，提供了“对照”；密切合作，使表达分析能够用于区域选择和突变验证；协作，提供小鼠和鱼类的功能复制；Co-I领导的FaceBase财团，将向颅面部社区快速传播数据和结果。我们相信这个项目有助于从整体上更好地理解如何使用序列数据来寻找因果变异和CLP的原因。 相关性：将全基因组(GWAS)关联信号转换为寻找特定突变对于将基因发现转化为临床应用至关重要。该项目将利用唇腭裂上的一个非常大的GWAS，其中包括父母样本，这些样本为检测这一重要出生缺陷的因果突变提供了独特的机会。它将为比较数据分析提供机会，这将对正在进行类似方法的其他研究有用。

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.