Identifying molecular pathways in childhood asthma pathogenesis by integrating newborn metabolic profiles and GWAS data

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PROJECT SUMMARY Childhood asthma is a common, burdensome disease for which there are currently no effective prevention strategies. This is due in part to our limited understanding of the molecular determinants of asthma pathogene- sis. As the development of asthma is highly influenced by genetic and environmental factors, assessment of both genetic and metabolomic profiles can improve our understanding of disease pathogenesis and identify potential targets for treatment and prevention. The overall research objective of this proposal is to elucidate metabolic and upstream genetic pathways underlying childhood asthma pathogenesis. Our central hypotheses are that metabolic profiles at birth are associated with subsequent development of childhood asthma and that this association is due in part to the effect of genetic variants on intermediate metabolic profiles and childhood asthma. To test these central hypotheses, we will pursue the following specific aims: 1) identify metabolic pro- files at birth associated with the development of childhood asthma, and 2) determine the genetic contribution to variation in metabolite concentrations at birth and identify genetic pathways linking metabolic profiles at birth with childhood asthma. To achieve Aim 1, we will capitalize upon a unique resource of longitudinal birth co- horts with newborn metabolic data and rich phenotypic data (n=6209 children). To achieve Aim 2, we will utilize genotypes for children within the largest of these cohorts to perform a metabolite genome-wide association study. We will then leverage these findings, along with summary statistics from the largest GWAS of childhood asthma performed to date, to perform a genetic co-localization analysis. The purpose of this K01 proposal is for Dr. Snyder to build on her prior training in maternal-child health epide- miology and experience with utilizing metabolomics data in large epidemiologic studies by taking on leadership roles in the conduct of epidemiologic studies, applying modern statistical methods for high-dimensional data, and receiving advanced training in genetic epidemiology so that she can more effectively address fundamental questions about upstream pathways of disease development. Through the comprehensive career development plan applied directly to the research, the complementary expertise of the mentorship team, and an outstanding institutional environment, Dr. Snyder will acquire the knowledge, skills, and resources necessary to advance her toward her long-term career goal of becoming a recognized leader in maternal-child health epidemiology, with a focus on integrating genetics and metabolomics in large epidemiologic studies to understand and pre- vent childhood respiratory diseases. The experience, training, and findings generated through this proposal will result in Dr. Snyder developing critical research skills to move toward independence and the submission of a highly competitive R01 application.