The Genetic and Proteomic Determinants of Pediatric Stature Development and their link to adult height and Type 2 Diabetes

Abstract

Stature is a key indicator of pediatric health, yet the molecular and metabolic architecture governing childhood growth remains incompletely defined. We conducted genome-wide association analyses of stature from birth to childhood (574,580 measurements; 72,704 Norwegian children) and integrated UK Biobank data (age 10 and adulthood). We uncovered life-stage shifts in the genetics of stature, identifying novel childhood-specific effects including variants near GLP1R with BMI-independent effects, and reveal three temporal clusters - infancy and childhood clusters enriched for endocrine and metabolic pathways, and a lifetime growth cluster enriched for skeletal biology. Proteome analysis revealed that prepubertal height is associated with widespread changes in the circulation, identifying 106 height-associated proteins and linking IGF1, IGF2, and IGFBP3 levels to childhood-height polygenic scores. Mendelian randomization showed that reduced fetal growth and taller prepubertal height increase type 2 diabetes risk, independent of adult stature. These findings uncover developmental stage-specific genetic and proteomic influences on child-growth and links to adult metabolic health.