Multigenic Dissection of Nonsyndromic Oral Clefts

描述(由申请人提供)：拟议的5年职业发展奖将提供生物信息学和大规模流行病学研究管理方面的培训和经验，并将为申请人在复杂疾病领域担任领导角色做好准备。拟议计划的优势之一是三位具有不同和独特专业领域的导师的承诺。他们将监督一个分阶段发展计划，在研究管理、复杂疾病的统计遗传学、生物信息学和计算生物学以及与公共卫生基因组学相关的伦理问题方面提供新的和增强的多学科技能。它将提供在致力于负责任地进行流行病学研究的职业生涯中取得成功所需的具体和多样化的技能，这些研究使用最先进的分子和计算方法来阐明复杂人类疾病的机制。在她的研究中，申请者将使用参加大规模出生缺陷监测研究的母亲和婴儿的DNA，通过一种经过验证的分析方法-贝叶斯网络的新应用，来调查非综合征性口腔裂(NOC)的多基因起源。在实现第一个目标时，她将确定和验证最有可能的网络，将孤立的NOC表型与候选母体和受试者的单核苷酸多态以及在多数种族/民族中的环境暴露联系起来。通过第二个目标，她将验证两种确定非孤立NOC表型的方法。最后，她将确定目标1和目标2中产生的模式(S)是否可以推广到少数族裔/族裔群体。该项目将提供一个框架，调查员将在此框架上为独立研究生涯做准备。此外，由于这是第一次在关联研究中同时考虑候选环境暴露和先前与NOC相关的几个候选基因中的SNP，这项工作有可能极大地推动NOC的研究。相关性：唇裂和/或腭裂是最常见的出生缺陷之一，对受影响的人有严重的身体、心理和经济后果。尽管如此，人们对这些异常的原因知之甚少，因为裂缝是遗传和环境风险因素的结果，而不是单一因素。这项拟议的研究有可能对我们的理解鸿沟做出独特的贡献，因为它使用了新的分析方法，允许同时检查许多潜在的风险因素。

DESCRIPTION (provided by applicant): The proposed 5-year career development award will provide training and experience in bioinformatics and the administration of large-scale epidemiologic studies and will prepare the applicant for a leadership role in the field of complex diseases. One of the strengths of the proposed plan is the commitment of three mentors with diverse and unique areas of expertise. They will oversee a phased development program to provide new and enhanced multidisciplinary skills in study management, the statistical genetics of complex disease, bioinformatics and computational biology, and the ethical issues associated with public health genomics. It will provide the specific and varied skills required to succeed in a career devoted to responsibly-conducted epidemiologic studies that employ state-of-the-art molecular and computational methods to elucidate the mechanisms of complex human diseases. In her research, the applicant will use DNA from mothers and infants enrolled in a large-scale birth defects surveillance study to investigate the multigenic origins of nonsyndromic oral clefts (NOC) using a novel application of a proven analytical approach, Bayesian networks. In accomplishing the first aim, she will identify and validate the most probable network linking the phenotype of isolated NOC to the candidate maternal and subject single nucleotide polymorphisms and environmental exposures among the majority race/ethnicity. Through the second aim, she will validate two approaches to phenotying non-isolated NOC. Finally, she will determine whether the model(s) generated in Aims 1 and 2 can be generalized to minority race/ethnicity groups. This project will provide the framework upon which the investigator will prepare for an independent research career. Additionally, by being the first investigation to concurrently consider the candidate environmental exposures and SNPs in several candidate genes previously associated with NOC in association studies, this work has the potential to move the study of NOC dramatically forward. Relevance: Cleft lip and/or cleft palate are among the most common birth defects have serious physical, psychological, and financial consequences for those affected. Despite this, little is known about the causes of these anomalies because clefts are the result of genetic and environmental risk factors, rather than a single factor. The proposed research has the potential to make a unique contribution to our understanding clefts because it uses novel analytical approaches that allow the simultaneous examination of many potential risk factors.