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

Abstract

Abstract Children born small for gestational age (SGA) face elevated risks of metabolic, cardiovascular, respiratory, and neurodevelopmental disorders, as well as premature mortality, yet the underlying mechanisms remain only partly understood. We analyze blood proteomic data from multiple birth cohorts to identify molecular pathways linked to SGA and to later-life lung function. We find that approximately one-third of SGA children exhibit a distinct molecular endotype marked by dysregulation of axon-guidance proteins in cord blood. In peripheral blood collected later in life, these proteins are inversely associated with contemporaneous spirometric restriction. Using GWAS data and an experimental sheep model, we obtain convergent evidence that axon-guidance genes are associated with spirometric indices (FEV 1 /FVC) at genome-wide significance and are broadly expressed during fetal development across multiple organs. These findings offer new insight into the developmental origins of chronic disease and highlight axon-guidance pathways as promising targets for investigating multiorgan morbidity.