Risk Genes and Environment Interactions in NTDs

描述（由申请人提供）：神经管缺陷（NTD），主要是脊柱裂和无脑畸形，由多种基因相互作用和环境暴露的复杂相互作用引起。经过30年的临床和基础研究，该领域仍然无法准确预测个体夫妇生下NTD的风险，叶酸（FA）如何预防NTD，是否或什么剂量的FA可能为他们提供有效的预防，或者是否有其他营养素/补充或干预，将提供更大的好处最近汇合的信息，从遗传小鼠模型，胚胎系统中的分子生物学和生物化学检测能力以及基因组学和计算遗传学的进展，现在为成功解决这种复杂的遗传疾病提供了足够的力量。 项目1将测试以下假设：1.罕见变异单核苷酸多态性（SNP）的组合将显示出对人类个体NTD风险定义有用的关联，以及2.认识到这些遗传模式与环境条件之间的相互作用，包括FA摄入和炎症或氧化/亚硝化应激的常见因素，可以进一步提高其预测价值。该项目将使用NTD患者DNA的深度重测序，通过临床和动物模型研究，靶向与NTD发病机制有关的约1,000个基因的人类对应物，以确定NTD患者中过度表达的罕见变异等位基因。这些将用于设计定制的SNP检测，用于筛选更大数量的患者，以分析单基因和与NTD的成对关联。计算建模将评估NTD相关SNP对关键发育和代谢途径的潜在影响。首先将使用体外和小鼠系统测定法对人类SNP关联的功能意义进行功能性测试，以确定对Wnt/PCP、FA代谢和氧化/亚硝化应激的影响，这些测定法也将用于验证和告知计算建模。 由于明显的NTD表型在人类和实验动物中很容易识别，NTD很可能是第一个可以深入理解基因-基因和基因-环境相互作用的复杂遗传疾病。这种疾病的进展可以提供有用的分析工具，用于识别与晚发型复杂遗传疾病（如精神分裂症和自闭症）相关的分子网络相互作用。

DESCRIPTION (provided by applicant): Neural tube defects (NTDs), primarily spina bifida and anencephaly, arise from a complex interplay of multiple gene interactions and environmental exposures. After 30 years of clinical and basic research, the field remains unable to accurately predict the risk for an individual couple of having a child affected by NTD, how folic acid (FA) works to prevent NTDs, whether or what dose of FA is likely provide effective prevention for them or whether there is another nutrient/supplement or intervention that would provide greater benefit The recent confluence of information from genetic mouse models, capabilities of molecular biological and biochemical detection in embryonic systems and advances in genomics and computational genetics now provides sufficient power to successfully address this complex genetic disorder. Project 1 will test the following hypotheses: 1. that combinations of rare variant single nucleotide polymorphisms (SNPs) will display associations useful for the definition of individual NTD risk in humans, and 2. that recognition of interactions between these genetic patterns with environmental conditions, including FA intake and factors common to inflammation or oxidative/nitrosative stress, can further increase their predictive value. This project will use deep resequencing of NTD patient DNA, targeted to human counterparts of some 1,000 genes implicated in NTD pathogenesis by clinical and animal model studies, to identify rare variant alleles that are overrepresented in NTD patients. These will be used to design custom SNP assays for screening larger patient numbers for analyses of single gene and pair-wise associations with NTD. Computational modeling will assess the potential impact of NTD associated SNPs on key developmental and metabolic pathways. The functional significance of SNP associations in humans will be functionally tested first for impact on Wnt/PCP, FA metabolism and oxidative/nitrosative stress using in vitro and mouse systems assays that will also be used to validate and inform computational modeling. Because the overt NTD phenotypes are readily recognized in humans and experimental animals, NTDs may well be the first complex genetic disorder for which gene-gene and gene-environment interactions can be understood in depth. Progress made for this disorder can provide useful analytical tools for identifying molecular network interactions relevant to later-onset complex genetic disorders, like schizophrenia and autism.