Maternal and Embryonic Causes of Spina Bifida

描述(申请人提供)：脊柱裂是一种相对常见的结构性畸形，与过高的发病率和死亡率有关。在大多数脊柱裂患者中，无法确定特定的病因(S)，在这组患者中，这种情况被认为是一种复杂的遗传特征。与其他复杂的人类特征一样，脊柱裂被认为受到常见基因变异的影响，这些变异个别地可能对风险只有很小到中等的影响。我们资助的研究旨在解决叶酸相关基因的常见变异导致脊柱裂风险的假设。我们对这一假设的评估考虑了母体和胚胎基因所扮演的角色，以及基因和环境风险因素的相互作用可能与脊柱裂的风险更相关，而不是任何一个易感基因座的独立主效应。在这项由研究人员发起的修订申请中，我们建议：(1)为新登记的受试者改变DNA提取样本的收集方法(从口腔刷子到唾液)，以及(2)增加从先前提供口腔刷子样本的登记研究受试者的唾液样本的收集。这些修订将增强我们实现研究计划近期和长期目标的能力，为我们当前和未来的研究提供更好的DNA来源(相对于口腔刷子)。具体地说，DNA质量的提高将减少测量误差(即减少基因分型错误，这可能导致基于家庭的研究中的差异偏见)，并提高基因分型呼叫率(即减少丢失数据)，这将对我们研究结果的有效性和精确度产生积极影响。此外，DNA产量的提高将使我们能够利用高密度基因分型平台，提供成本和时间效率，并将增强我们的DNA库的长期和科学用途。与公共卫生相关：神经管缺陷，包括脊柱裂，是常见的严重出生缺陷，每年影响全球约324,000名新生儿(1)和美国的3,000名孕妇。我们资助的研究将提供有关影响脊柱裂风险的因素的重要信息，最终将允许进行更准确的遗传咨询和改进预防这种疾病的方法。对资助研究的拟议修订旨在增加可用于我们调查的DNA的数量和质量，将提高实现研究目标的可能性。

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. Our funded study is designed to address the hypothesis that common variants in folate-related genes contribute to the risk of spina bifida. Our evaluation of this hypothesis considers 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. In this investigator-initiated, revision application, we propose to: (1) change the method used for the collection of samples for DNA extraction (from buccal brushes to saliva) for newly enrolled subjects, and (2) add the collection of a saliva sample from enrolled study subjects who previously provided a buccal brush sample. These revisions will enhance our ability to achieve the immediate and long- term goals of our research program, by providing an improved source of DNA (relative to buccal brushes) for our current and future investigations. Specifically, improvement in DNA quality will result in decreased measurement error (i.e. decreased genotyping errors, which can lead to differential bias in family-based studies) and improved genotyping call rates (i.e. less missing data), which will have a positive impact on the validity and precision of our study findings. Further, improved DNA yield will allow us to take advantage of high-density genotyping platforms, which offer both cost and time efficiency, and will enhance the long-term, scientific usefulness of our DNA bank. PUBLIC HEALTH RELEVANCE: Neural tube defects, including spina bifida, are common, serious birth defect that affects approximately 324,000 births worldwide (1) and 3,000 pregnancies in the United States annually. Our funded study will provide important information regarding the factors that influence the risk of spina bifida that, ultimately, will allow for more accurate genetic counseling and improved methods for preventing this condition. The proposed revisions to the funded study, which are aimed at increasing the quantity and quality of the DNA available for our investigations, will improve the likelihood that the study goals will be realized.