International Genetic Epidemiology of Oral Clefts

描述(调查者提供)：在R01-DE-014581(2003年至2008年)的初期，我们成功地从5个地点(马里兰州、新加坡、台湾和中国的2个地点)招募病例，成功地进行了一项多中心的口腔裂(包括唇裂，CL；唇腭裂，CLP；以及腭裂，CP)的遗传病因学研究。我们已经组装了1497个病例-亲本三联体，并成功地在候选基因和候选通路上对5412个单核苷酸多态(SNP)标记进行了基因分型。已有几个基因(包括一些公认的候选基因和一些新的基因)被确定为影响口裂风险的基因，其中一些基因表现出明显的亲本效应和与常见环境风险因素的潜在交互作用。这一竞争性更新申请将扩展并建立在我们之前的研究以及由我们的霍普金斯小组和其他4个小组组成的财团进行的全基因组关联研究(GWAS)的基础上。我们提出了4个具体目标：1)通过组合分析，然后精细绘制来自美国、亚洲、德国和爱尔兰的新病例-父母三组的地图，将我们使用病例-父母三组的结果与德国的病例对照研究的结果进行比较。2)考虑评估基因-环境(GxE)与常见母亲暴露(母亲吸烟、饮酒和补充维生素)之间的交互作用的模型，方法是使用我们的GWAS病例-父母三人组和德国病例分析整个基因组范围的SNP阵列。我们还将与犹他州立大学的芒格博士(该项目的长期顾问)合作，测量唇裂患者母亲的血清样本中维生素B12和甲基丙二酸的水平，以评估与一碳代谢和DNA甲基化相关的生物学模型。3)通过扩大病例家系，将3个群体(马里兰州、台湾和新加坡)的祖父母包括在内，进一步研究表明父母原籍效应的证据的基因(可能反映基因印记)。我们还将测试在这项研究中确定的选定基因中的差异甲基化模式。4)我们将对显示单独作用的证据的基因进行深入的重新测序研究，仅在环境暴露存在时或仅当通过父母之一传播时，以确定基因及其顺式调控区的所有变异，特别是罕见的变异，可能控制口裂的风险。 公共卫生相关性：该项目将结合两项关于非综合征性口腔裂(唇裂、唇腭裂和腭裂)的全基因组研究的数据，以确定可能在控制风险方面单独起作用的基因，可能与常见的母亲接触(母亲吸烟、饮酒和维生素使用)相互作用的基因，以及显示母亲和父亲不同传播的证据可能反映印记的基因。

DESCRIPTION (provided by investigator): During the initial period of R01-DE-014581 (2003-2008), we successfully conducted a multi-center, international study on the genetic etiology of oral clefts (including cleft lip, CL; cleft lip and palate, CLP; and cleft palate, CP) by recruiting cases from 5 sites (Maryland, Singapore, Taiwan, and 2 sites in China). We have assembled 1497 case-parent trios, and successfully genotyped 5412 single nucleotide polymorphic (SNP) markers in candidate genes and candidate pathways on subsets of trios. Several genes have been identified as influencing risk to oral clefts (including some recognized candidate genes and some novel ones), and some genes show distinct parent-of-origin effects and potential interaction with common environmental risk factors. This competitive renewal application will extend and build upon our previous studies plus a genome wide association study (GWAS) from a consortium of our Hopkins group and 4 other groups. We propose 4 specific aims: 1) To compare our GWAS findings using case-parent trios with those of a German case-control study through combined analysis followed by fine mapping of new case-parent trios from the US, Asia, Germany and Ireland. 2) To consider models for assessing gene-environment (GxE) interactions with common maternal exposures (maternal smoking, alcohol consumption and vitamin supplementation) by analyzing the entire genome wide SNP array using our GWAS case-parent trios and the German cases. We will also collaborate with Dr. Munger of Utah State University (long time consultant to this project) to measure levels of vitamin B12 and methylmalonic acid in serum samples from mothers of cleft cases to evaluate biological models relevant to one carbon metabolism and DNA methylation. 3) To further investigate genes showing evidence of parent- of-origin effects (which may reflect genetic imprinting) by extending case families to include grandparents in 3 populations (Maryland, Taiwan and Singapore). We will also test for differential methylation patterns in selected genes identified during this study. 4) We will conduct deep resequencing studies of genes showing evidence of acting alone, only in the presence of environmental exposures or only when transmitted through one parent to identify all variants in genes and their cis-regulatory regions, especially rare variants, that may control risk to oral clefts. PUBLIC HEALTH RELEVANCE: This project will combine data from two genome wide studies of non-syndromic oral clefts (cleft lip, cleft lip & palate, and cleft palate) to identify genes that may act alone in controlling risk, genes that may interact with common maternal exposures (maternal smoking, alcohol consumption and vitamin use), and genes that show evidence of different transmission from mothers and fathers which may reflect imprinting.