Early-Life Genetic Determinants of Height and their Time-Dependent Links to Type 2 Diabetes
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Stature in infancy and childhood is a fundamental indicator of pediatric health, yet its genetic determinants are incompletely understood. We performed genome-wide association studies of childhood length/height across 12 time points from birth to eight years, representing 574,580 measurements from up to 72,704 children in the Norwegian Mother, Father and Child Cohort Study. We identified 179 genetic loci, including 19 novel signals for human height. To assess the development of genetic signals across the life course, we complemented our analysis with UK Biobank data on height at age 10 (n = 332,021) and adulthood (n = 458,303) which revealed three clusters with distinct temporal trajectories replicating in the ALSPAC cohort: infancy, childhood, and lifetime growth. Infancy and childhood clusters were enriched for genes involved in endocrine and metabolic pathways whereas the lifetime growth loci mapped to skeletal development and growth disorders. Mendelian randomization analyses demonstrated that reduced fetal growth confers increased type 2 diabetes risk, while taller prepubertal stature predicts higher metabolic risk independent of adult height. Polygenic scores combined with parental height improved prediction of childhood stature. These findings uncover developmental stage-specific genetic influences on growth and highlight mechanistic links between early-life stature and type 2 diabetes.
