Sequencing of significant signals from cleft lip GWAS

描述（由申请人提供）：唇腭裂（CLP）是常见的出生缺陷，病因复杂。大约70%的人出生时有孤立的裂缝，没有其他结构或认知异常。每700名新生儿中就有1人会出现裂缝，需要进行手术、营养、牙科、语言和行为干预。他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还与所有原因导致的死亡增加以及精神健康障碍和癌症风险增加有关。现在，通过使用家族收集、仔细的表型分析和全基因组关联研究（GWAS）的组合来鉴定与复杂性状的病因学相关的常见变异是可行的。下一个关键的步骤，从关联到特定的因果变异识别一直很困难，虽然有一个成功的CLP研究。通过对相关区域的深度序列分析以及随后通过表达和功能分析的确认，将极大地促进下一步。我们将使用最近完成的一个大型（1900例/父母三人组）GWAS，结合来自3个较小的已发表GWAS研究的样本和数据，以选择深度测序的区域。四个良好复制的基因座/基因将形成这项工作的核心（IRF 6，MAFB，ABCA 4和8 q24），另外两个基因（VAX 1和FOXE 1）也具有令人信服的支持数据。一个强大的团队已经组建起来开展这项工作，该项目有许多新颖和创新的特点，包括：3500例病例的父母样本，使其能够使用传播不平衡测试进行分析和检测从头罕见变异; IRF 6中确认的病因变异提供了“对照”;密切合作，使表达分析被用于区域选择和突变验证;合作，以提供在小鼠和鱼类的功能复制; Co-I对FaceBase联盟的领导，该联盟将为颅面社区提供快速的数据和结果传播。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寻找致病变异和CLP的原因。 相关性：将全基因组（GWAS）关联信号转换为发现特定突变对于遗传发现转化为临床实用性至关重要。该项目将利用一个非常大的GWAS对唇腭裂，其中包括父母的样本，提供了独特的机会，检测这种重要的出生缺陷的因果突变。它将为比较数据分析提供机会，这将有助于采用类似方法的其他研究。

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.