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

项目摘要/摘要 非综合征性唇裂是世界范围内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裂的风险中起主要作用；事实上，几个遗传风险基因已被 到目前为止，已确认身份。然而，这些基因座累积起来只解释了部分遗传性，而且对于大多数遗传性来说 具体的因果变异还没有确定。此外，最近的研究表明，裂隙 亚型(即单侧唇裂、单侧唇裂、单侧唇裂 完整性)可能具有部分重叠和部分不同的病因，尽管共享的和 裂隙亚型的非共有遗传结构还没有被很好地理解。此外，母体环境 众所周知，怀孕期间的暴露(即吸烟、饮酒和叶酸)会影响唇裂风险。 并可能与遗传因素相互作用，作为潜在的唇裂倾向的一部分。这项提案将寻求填补 关于基因变异及其与母亲暴露的相互作用导致公开的 裂隙的形式。该项目将包括对我们之前收集的队列的现有数据的分析，包括 有口面部裂的病例、其直系亲属和无唇裂史的对照。我们将使用 这些数据用于执行全基因组关联研究和有针对性的基因与环境的相互作用 口面部裂隙及其亚型的分析。了解口面部裂隙的遗传结构可能 最终改善对风险和复发的预测，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.