Association of IGF-1 Levels With Height From Childhood to Adulthood: An Observational and Mendelian Randomization Study.

Abstract

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. To explore 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 genome-wide association study (GWAS), and their effects on adult height were identified in the GIANT Consortium GWAS, excluding UK Biobank (Non-Hispanic White: N = 1 176 465; African descent: N = 168 191; South Asian: N = 49 032; East Asian: N = 361 369; Hispanic: 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 to 11 years or a genetic risk score (GRS) for IGF-1, with repeated height measurements at ages 7 to 17 years, adjusting for sex, body mass index (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 to 8 years and IGF-1 GRS were positively associated with height at ages 7 to 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.