Multigenic Dissection of Nonsyndromic Oral Clefts

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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.