Maternal and Embryonic Causes of Spina Bifida

脊柱裂是一种相对常见的结构性畸形，与过度的发病率和 死亡率。在大多数脊柱裂患者中，无法确定特定的病因(S)，并且 在这组患者中，这种情况被认为是一种复杂的遗传特征。与其他复合体一样 人类的特征，脊柱裂被认为是受常见的遗传变异影响的，个别的，可能 对风险只有很小到中等的影响。然而，识别这种变异的努力受到了阻碍。 因为缺乏复制。这至少部分归因于疾病病因学模型过于简单化。 实验设计和样本量不足。本申请中提出的研究旨在 尽量减少这些限制，同时解决主要的研究假设：叶酸相关的常见变体 基因导致了脊柱裂的风险。我们对这一假设的评估将考虑所扮演的角色 母体和胚胎的基因型，以及基因和胚胎之间相互作用的可能性 环境风险因素与脊柱裂的风险可能比独立的主要因素更相关。 任何一个易感基因座的影响。这一经过两次修订的具有竞争力的续订申请建立在我们的 之前的工作是：(1)扩大我们的家族集合，(2)增加叶酸相关基因的数量 进行评估，并从单SNP方法转变为每个基因多SNP方法，(3)纳入新的 用于评估复杂相互作用的方法，以及(4)扩展我们最近开发的可能性- 基于评估母体和胚胎遗传效应的方法，以允许丢失数据， 基因分型错误以及基因-环境和基因-基因相互作用。这些研究将有助于确定 脊柱裂风险与叶酸相关基因变异的关系。这样的理解将会 为遗传咨询提供更好的内容，包括基于基因的可能性，风险- 评估，并为针对这一常见、严重畸形的新的预防战略奠定基础。

Spina bifida is a relatively common, structural malformation that is associated with excess morbidity and mortality. A specific etiologic agent(s) cannot be identified in the majority of individuals with spina bifida, and in this group of patients the condition is believed to be a genetically complex trait. As with other complex human traits, spina bifida is thought to be influenced by common genetic variants that, individually, may have only a small to moderate effect on risk. However, efforts to identify such variants have been hampered by lack of replication. This is, at least in part, attributable to overly simplistic models of disease etiology, poor experimental design and insufficient sample size. The studies proposed in this application are designed to minimize these limitations while addressing the primary study hypothesis: common variants in folate-related genes contribute to the risk of spina bifida. Our evaluation of this hypothesis will consider the roles played by both the maternal and embryonic genotype, and the possibility that the interplay of genes and environmental risk factors may be more relevant to the risk of spina bifida than is the independent main effect of any one susceptibility locus. This twice revised, competitive renewal application builds on our previous work by: (1) extending our collection of families, (2) increasing the number of folate-related genes to be evaluated, and moving from a single-SNP to a multiple-SNP per gene approach, (3) incorporating new methods for the assessmentof complex interactions, and (4) extending our recently developed, likelihood- based approach for evaluation of maternal and embryonic genetic effects to allow for missing data, genotyping errors and both gene-environment and gene-gene interactions. These studies will help to define the relationship between spina bifida risk and variation in folate-related genes. Such an understanding will provide improved content for genetic counseling, including the possibility of genotype-based, risk- assessment, and the foundation for novel new prevention strategies for this common, serious malformation.