Association of IGF-1 levels with height from childhood to adulthood: An observational and Mendelian randomization study

Growth hormone therapy, which increases circulating levels of insulin-like growth factor 1 (IGF-1), effectively enhances adult height in children with idiopathic short stature, although with varying responses. This raises the question whether normal IGF-1 variation within a population is causally associated with height across childhood and in adulthood. We used Two-Sample Mendelian Randomization (MR) to assess the causal effect of serum IGF-1 on adult height. Genetic instruments for IGF-1 were derived from a UK Biobank GWAS, and their effects on adult height were identified in the GIANT consortium GWAS, excluding UK Biobank (Non-Hispanic Whites: N=1,176,465; African Descent: N=168,191; South Asians: N= 49,032; East Asians: N=361,369; Hispanics: N=58,709). Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated cross-sectional and longitudinal associations between measured IGF-1 levels at ages 7-11 years or a genetic risk score (GRS) for IGF-1, with repeated height measurements at ages 7-17 years, adjusting for sex, BMI, and pubertal stage. Inverse variance-weighted MR showed that a 1 SD increase in IGF-1 confers 0.09 SD taller adult height, which persisted after adjusting for childhood BMI. In ALSPAC, both measured IGF-1 levels at ages 7-8 years and IGF-1 GRS were positively associated with height at ages 7-17 years at both cross-sectional and longitudinal analyses. Our findings suggest that IGF-1 normal variation has small effects on height in childhood and on final adult height.