Host genetics, early-life microbiome, and childhood asthma: MARC-43 Boston

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Project Abstract Recent studies report probabilistic associations between the early-life microbiome and various child health outcomes (e.g., obesity, asthma), suggesting potential insights into pathogenesis and subsequent, targeted development of preventive interventions. However, the causal role of the early-life microbiome on child health remains unclear. Our preliminary work has applied state-of-art statistical genetics and causal inference approaches to large genetics and microbiome data in our ECHO-supported cohorts, demonstrating: 1) host genetic loci for airway Streptococcus across racial/ethnic populations, 2) host genetic loci for gut microbiome and significantly enriched biological pathways (e.g., regulation of neuron development, glucuronate interconversions), and 3) relationship of gut Bacteroides with obesity and asthma risk. Our central hypothesis is that the genetically driven gut and upper airway microbiome in the first two years of life has a causal role in the development of child health outcomes, such as obesity and airway outcomes. This UG3/UH3 project will test this innovative hypothesis by applying the latest statistical genetics and epidemiological methods—e.g., microbiome genome-wide association study (mGWAS)— to large ECHO genetics, microbiome, and extensive clinical and environmental data. By using ECHO core data elements, Aim 1 will generate mGWAS summary statistics to enable researchers to examine the causal role of the early-life microbiome on child health outcomes. For example, by using the mGWAS and Mendelian randomization approaches, we will determine the causal role of the gut and nasal airway microbiome (during age 0-1.9 years) in the risk of developing childhood obesity. By using specialized airway outcome data, Aim 2 will determine whether the genetically driven gut and nasal microbiome has a causal effect on the development of asthma (and its major phenotypes) and on lower lung function in later childhood. Aim 3 will maximize the retention of existing ECHO Cohort Protocol (ECP) participants, with emphasis on diversity, and implement the ECP with high fidelity. (To date, in MARC-43 Boston participants, ECP retention is 100%, with >80% data completeness.) The proposed project will serve as a national research resource for examining the causal role of early-life microbiome in various childhood health outcomes. Furthermore, the project will provide a robust evidence base for the future development of targeted microbiome interventions to prevent childhood obesity and asthma. The investigators are NIH-funded researchers with international expertise in all relevant fields (e.g., epidemiology, statistical genetics, microbiome, childhood obesity, asthma). The project matches well with the goals of the ECHO Program.