International Genetic Epidemiology of Oral Clefts

描述（由研究者提供）：在R 01-DE-014581的初始阶段（2003-2008），我们通过从5个研究中心（马里兰州、新加坡、中国台湾和中国的2个研究中心）招募病例，成功开展了一项关于唇腭裂（包括唇裂、CL、唇腭裂、CLP和腭裂、CP）遗传病因的多中心国际研究。我们已组装了1497个病例双亲三重奏，并成功对三重奏子集的候选基因和候选途径中的5412个单核苷酸多态性（SNP）标记进行了基因分型。一些基因已被确定为影响唇腭裂的风险（包括一些公认的候选基因和一些新的），一些基因显示出独特的父母的原产地的影响和潜在的相互作用与常见的环境风险因素。这项竞争性更新申请将扩展并建立在我们以前的研究以及我们霍普金斯小组和其他4个小组组成的联盟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）通过合并分析，然后对来自美国、亚洲、德国和爱尔兰的新病例-父母三人组进行精细绘图，将我们使用病例-父母三人组的GWAS结果与德国病例-对照研究的结果进行比较。2)通过使用我们的GWAS病例-父母三人组和德国病例分析全基因组SNP阵列，考虑评估基因-环境（GxE）与常见母体暴露（母体吸烟、饮酒和维生素补充）相互作用的模型。我们还将与犹他州州立大学的Munger博士（该项目的长期顾问）合作，测量唇裂病例母亲血清样本中的维生素B12和甲基丙二酸水平，以评估与一碳代谢和DNA甲基化相关的生物模型。3)通过扩展病例家族以包括3个人群（马里兰州、中国台湾和新加坡）的祖父母，进一步研究显示出来源父母效应证据的基因（可能反映遗传印记）。我们还将测试在本研究中确定的选定基因的差异甲基化模式。4)我们将对显示单独作用的证据的基因进行深入的重测序研究，仅在环境暴露的情况下或仅在通过一个父母传播时，以确定基因及其顺式调节区域的所有变体，特别是罕见的变体，这些变体可能控制口裂的风险。

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.