International Genetic Epidemiology of Oral Clefts

​我们组装了1497个病例-亲本三人组，并成功地在三人组亚群的候选基因和候选途径中对5412个单核苷酸多态性（SNP）标记进行了基因分型。已经确定了几个影响唇裂风险的基因（包括一些已知的候选基因和一些新的基因），一些基因表现出明显的亲本起源效应和与常见环境风险因素的潜在相互作用。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我们的霍普金斯小组和其他4个小组联合进行的基因组广泛关联研究（GWAS）的基础上。我们提出4个具体目标：1)通过对来自美国、亚洲、德国和爱尔兰的新病例-父母三人组进行组合分析，将我们的GWAS研究结果与德国的病例对照研究结果进行比较。2)通过分析我们的GWAS病例-父母三人组和德国病例的全基因组SNP阵列，考虑评估基因-环境（GxE）相互作用与常见母体暴露（母体吸烟、饮酒和补充维生素）的模型。我们还将与犹他州立大学的Munger博士（该项目长期顾问）合作，测量唇腭裂母亲血清样本中维生素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)通过在3个人群（马里兰州、台湾和新加坡）中扩大病例家族，包括祖父母，进一步研究显示父母起源效应证据的基因（这可能反映了遗传印记）。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证据的基因进行深度重测序研究，仅在存在环境暴露或仅通过父母一方传播的情况下，以确定基因及其顺式调控区域的所有变异，特别是可能控制唇裂风险的罕见变异。

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.