Genetic Epidemiology of Neural Tube Defects

描述（由申请人提供）：在美国，最常见（1/1000活产）的严重致残性出生缺陷是神经管缺陷（NTD）。NTD的原因尚不清楚，可能是遗传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参与其中。神经管缺陷协作研究是NTD遗传研究的丰富资源，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NTD的潜在遗传病因，必须利用多种分析方法，包括定向候选基因研究和定位克隆。目前用于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。具体而言，在NTD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不能被纳入当前模型。该建议的第一个目标是扩展对数线性模型，利用基因型信息从未受影响的兄弟姐妹，以改善推理缺失的父母数据的期望最大化算法，并使用由此产生的对数线性模型来测试关联NTD候选基因。其次，定位克隆策略以前从未被用于NTD的研究，主要是由于缺乏多重家庭。将利用NTD合作研究的丰富遗传和环境数据，对迄今为止的第一个NTD基因组筛选进行连锁分析和条件连锁分析。这些方法的综合是必要的，以阐明NTDs的病因。

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.