Genetic Epidemiology of Neural Tube Defects

描述(申请人提供)：在美国，最常见的(1/1000活产儿)致残的出生缺陷是神经管缺陷(NTDS)。NTDS的原因尚不清楚，很可能是遗传因素和环境因素之间复杂相互作用的结果。母体效应或印记也可能涉及其中。神经管缺陷合作研究为NTDS的遗传学研究提供了丰富的资源，收集了1000多个家庭的详细表型、遗传和环境风险因素数据。在这项研究中，为了有效地剖析NTDS的潜在遗传病因，必须使用多种分析方法，包括定向候选基因研究和定位克隆。目前候选基因研究的统计方法未能充分利用NTD数据集中可用的家族结构。具体地说，在NTDS和其他出生缺陷的情况下，通常会确定其他未受影响的兄弟姐妹。对数线性模型是一种基于回归的模型，非常适合研究具有多因素病因的疾病。然而，来自未受影响的兄弟姐妹的潜在有价值的数据无法纳入当前模型。该建议的第一个目标是通过利用未受影响的兄弟姐妹的基因信息来扩展对数线性模型，以改进期望最大化算法对缺失父母数据的推断，并使用所得到的对数线性模型来测试NTD候选基因的关联性。其次，定位克隆策略以前从未被用于NTDS的研究，这主要是由于多重家族的稀少。将利用来自NTD合作研究的丰富的遗传和环境数据，对NTD迄今的第一个基因组筛查进行连锁分析和条件连锁分析。这些方法的综合对于阐明NTDS的病因是有必要的。

DESCRIPTION (provided by applicant): The most common (1/1000 live births) severally disabling birth defect in the United States is neural tube defects (NTDs). The causes of NTDs are unknown and are likely to be a result of complex interactions between genetic and environmental factors. Maternal effects or imprinting may also be involved. The Neural Tube Defects Collaborative Study serves as a rich resource for genetic studies of NTDs, with detailed phenotypic, genetic and environmental risk factor data collected on over 1000 families. To effectively dissect the underlying genetic etiology of NTDs in this study, multiple analytic approaches must be utilized including directed candidate gene studies and positional cloning. Current statistical methods for candidate gene studies fail to take full advantage of the family structure available in the NTD dataset. Specifically, in the case of NTDs and other birth defects, additional unaffected siblings are often ascertained. The log-linear model is a regression-based model, well suited for studying diseases with multifactorial etiology. However, potentially valuable data from unaffected siblings cannot be incorporated into the current model. The first goal of the proposal is to extend the log-linear model by utilizing genotype information from unaffected siblings to improve inference of missing parental data with the Expectation Maximization algorithm and to use the resulting log-linear model to test for association in NTD candidate genes. Secondly, a positional cloning strategy has never before been employed in the study of NTDs, primarily due to the paucity of multiplex families. Linkage analyses and conditional linkage analyses of the first genomic screen of NTD to date will be performed, taking advantage of the wealth of genetic and environmental data from the NTD collaborative study. A synthesis of these approaches is warranted for elucidating the etiology of NTDs.