Identifying causal mechanisms of metabolites in family-based association studies of childhood asthma

Abstract Asthma is a chronic disease with a substantial public health burden. Asthma has both genetic and environmental risk factors; however, metabolomics has the distinct advantage of reflecting the net result of genomic and environmental influences by profiling the small molecules (i.e., metabolites) that reflect the complex physiological processes manifesting as difference in clinical features observed in asthma. The global metabolome is therefore well-suited to capture both unique and common disease mechanisms that drive a range of lung function. It is critical to understand the genetics underlying the metabolome and lung function for accurate classification and improved treatment responsiveness across the spectrum of asthma. The Genetic Epidemiology of Asthma in Costa Rica (GACRS) cohort recruited children with mild-to-moderate asthma from the Central Valley of Costa Rica. This area represents a Hispanic population which has one of the highest prevalences of asthma in the world (24% in children), making it uniquely suited for the exploration of the metabolomic underpinnings of asthmatic lung function. GACRS is a family-based study, which provides a unique opportunity to examine the causal relationship between SNPs, metabolites, and lung function in a framework that is robust to population stratification and phenotypic misspecification and can accommodate unbiased screening steps. The objective of this proposal is to identify pleiotropic associations of metabolites and lung function (i.e., SNPs associated with both lung function and at least one metabolite) (Aim 1), identify metabolomic determinants of lung function (Aim 2), and examine the genetic effect on lung function as mediated by the metabolites (Aim 3) among Hispanic children with asthma in GACRS and the Childhood Asthma Management Program (CAMP) with replication in Hispanic, Black, and Non-Hispanic White children in VDAART and replication/ generalizability to adults (Hispanic, Black and Non-Hispanic White) in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program.