Maternal and Embryonic Causes of Spina Bifida

描述（由申请人提供）：脊柱裂是一种相对常见的结构性畸形，与高发病率和死亡率相关。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，这种情况被认为是一种遗传复杂的特征。与其他复杂的人类特征一样，脊柱裂被认为受到常见遗传变异的影响，这些遗传变异单独对风险的影响可能很小。然而，由于缺乏复制，鉴定此类变体的努力受到阻碍。这至少部分归因于疾病病因学模型过于简单、实验设计不佳和样本量不足。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：叶酸相关基因的常见变异导致脊柱裂的风险。我们对这一假设的评估将考虑母体和胚胎基因型所起的作用，以及基因和环境危险因素的相互作用可能比任何一个易感基因的独立主效应与脊柱裂的风险更相关的可能性。这个经过两次修订的竞争性续期申请以我们以前的工作为基础，包括：（1）扩展我们的家族集合，（2）增加待评估的叶酸相关基因的数量，并从单SNP方法转向每个基因多SNP方法，（3）纳入用于评估复杂相互作用的新方法，以及（4）扩展我们最近开发的，基于可能性的方法，用于评估母体和胚胎遗传效应，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。这种理解将为遗传咨询提供更好的内容，包括基于基因型的风险评估的可能性，以及这种常见的严重畸形的新预防策略的基础。

DESCRIPTION (provided by applicant): 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 assessment of 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.