Investigating the role of genes, maternal exposures, and interactions on orofacial clefts

项目总结/摘要 非综合征性口面裂是世界上最常见的出生缺陷之一。遗传变异是 被认为在非综合征性唇腭裂的风险中起主要作用;事实上，几个遗传风险位点已经被 识别，至今。然而，这些基因座累积起来只能解释部分遗传力， 基因座，具体的致病变种尚未确定。此外，最近的研究表明， 亚型（即，单纯唇裂、唇裂伴腭裂、单纯腭裂，以及由偏侧性和 完整性）可能有部分重叠和部分不同的病因，虽然共享和 不共享的裂亚型的遗传结构还没有被很好地理解。此外，产妇环境 暴露（即，怀孕期间吸烟、饮酒和叶酸）会影响唇裂风险 并可能与遗传因素相互作用，作为潜在的裂缝倾向的一部分。该提案将寻求填补 关于遗传变异及其与母体暴露的相互作用的知识差距，导致明显的 裂缝的形式。该项目将包括对我们先前收集的队列的现有数据的分析， 例口面裂患者及其直系亲属，对照组无唇裂病史。我们将使用 这些数据用于进行全基因组关联研究和靶向基因与环境的相互作用 分析口面裂和亚型。了解口面裂的遗传结构， 最终导致改善风险和复发的预测，并可能为新的预防或治疗提供信息。 干预措施。

Project Summary/Abstract Non-syndromic orofacial clefts are one of the most common birth defects worldwide. Genetic variation is thought to play a major role in risk of non-syndromic clefts; indeed, several genetic risk loci have been identified, to date. However, these loci cumulatively explain only part of the heritability, and for most of these loci, the specific causal variants have not yet been determined. Moreover, recent work has suggested that cleft subtypes (i.e., cleft lip alone, cleft lip with cleft palate, cleft palate alone, and subtypes defined by laterality and completeness) may have partially overlapping and partially distinct etiologies, although the shared and unshared genetic architectures of cleft subtypes are not well understood. Furthermore, maternal environmental exposures (i.e., smoking, alcohol consumption, and folate) during pregnancy are known to influence cleft risk and may interact with genetic factors as part of the underlying cleft liability. This proposal will seek to fill the gap in knowledge regarding the genetic variants and their interactions with maternal exposures leading to overt forms of clefts. This project will include analyses of existing data on our previously collected cohort comprising cases with orofacial clefts, their immediate family members, and controls with no history of clefts. We will use these data to perform genome-wide association studies and targeted gene-by-environmental interaction analyses for orofacial clefts and subtypes. Understanding the genetic architecture of orofacial clefts may ultimately lead to improved prediction of risk and recurrence, and may inform new preventive or therapeutic interventions.