Multicohort analysis unveils role for axon guidance pathways linking small for gestational age to spirometric restriction

Children born small for gestational age (SGA) are at risk for the development of metabolic, cardiovascular, respiratory, and neurodevelopmental diseases and premature mortality, but the underlying mechanisms are unknown. We analyze blood proteomic data from several birth cohorts to elucidate molecular mechanisms related to SGA and subsequent lung function outcomes in later life. We found that one-third of children born SGA manifest a distinct molecular endotype characterized by axon guidance protein dysregulation in cord blood. In later life, peripheral blood, these proteins were inversely related to concurrent spirometric restriction. We obtained orthogonal evidence from GWAS data and an experimental sheep model to show axon guidance genes are associated with spirometry measurements (FEV1/FVC) at genome-wide significance and are commonly expressed during fetal development of multiple organs. Our findings provide new insights into the developmental origins of chronic diseases and pave the way for further study of axon guidance cues in multiorgan morbidity. This Dryad repository contains the scRNA-Seq dataset for the sheep model of the linked manuscript.