Maternal and Embryonic Causes of Spina Bifida

脊柱裂是一种相对常见的结构性畸形， mortality.在大多数脊柱裂患者中无法确定特定的病原体， 在这组患者中，该病症被认为是遗传上复杂的特征。与其他复杂 人类的特征，脊柱裂被认为是由共同的遗传变异，个别影响， 对风险只有轻微到中等程度的影响。然而，识别此类变体的努力受到了阻碍 缺乏复制。这至少部分归因于过于简单的疾病病因学模型， 实验设计和样本量不足。本申请中提出的研究旨在 最大限度地减少这些限制，同时解决主要研究假设：叶酸相关的常见变异 基因会增加脊柱裂的风险。我们对这一假设的评估将考虑在这一假设中所扮演的角色。 母亲和胚胎基因型，以及基因和 环境风险因素可能与脊柱裂的风险更相关，而不是独立的主要因素。 任何一个易感基因座的影响。这两次修订，竞争性续期申请建立在我们的 以前的工作：（1）扩大我们的家庭收集，（2）增加叶酸相关基因的数量， （3）将新的SNP整合到每个基因的多SNP方法中， 复杂相互作用的评估方法，以及（4）扩展我们最近开发的，可能性- 用于评价母体和胚胎遗传效应的基于方法，以考虑缺失数据， 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之间的关系。这样的理解将 为遗传咨询提供更好的内容，包括基于基因型的可能性，风险， 评估，并为这种常见的严重畸形的新的预防策略奠定基础。

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.