Multigenic Dissection of Nonsyndromic Oral Clefts

描述（由申请人提供）：拟议的5年职业发展奖励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的领导角色做好准备。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的发展计划，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的流行病学研究的职业生涯中取得成功所需的具体和各种技能，这些研究采用最先进的分子和计算方法来阐明复杂的人类疾病的机制。在她的研究中，申请人将使用在大规模出生缺陷监测研究中登记的母亲和婴儿的DNA来研究非综合征性唇腭裂（NOC）的多基因起源，并使用一种经过验证的分析方法-贝叶斯网络的新应用。为了实现第一个目标，她将确定并验证大多数种族/民族中将分离的NOC表型与候选母体和受试者单核苷酸多态性和环境暴露联系起来的最可能的网络。通过第二个目标，她将验证两种方法来表型非分离NOC。最后，她将确定目标1和目标2中生成的模型是否可以推广到少数种族/民族群体。这个项目将为研究者准备一个独立的研究生涯提供框架。此外，作为第一个同时考虑候选环境暴露和先前在关联研究中与NOC相关的几个候选基因的snp的研究，这项工作有可能极大地推进NOC的研究。相关性：唇裂和/或腭裂是最常见的出生缺陷之一，对那些受影响的人有严重的生理、心理和经济后果。尽管如此，对这些异常的原因知之甚少，因为唇裂是遗传和环境风险因素的结果，而不是单一因素。拟议的研究有可能对我们理解裂缝做出独特的贡献，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.