Lower Genetically Predicted Circulating Insulin-like Growth Factor-1 is Associated with a Higher Risk of Adolescent Idiopathic Scoliosis

Study Design. A two-sample Mendelian randomization (MR) analysis. Objective. To evaluate the association between insulin-like growth factor-1 (IGF-1) and adolescent idiopathic scoliosis (AIS) Summary of Background Data. The IGF-1/growth hormone axis has been implicated in AIS development, yet discordant findings exist regarding an association between serum IGF-1 and AIS. Methods. Summary statistics were retrieved from two genome-wide association studies; one investigating IGF-1 (389,525 patients) the other investigating AIS (7,956 patients). MR analysis was performed leveraging complementary methods including inverse variance weighting (IVW), MR Egger, simple mode, weighted median, and weighted mode. Sensitivity analyses included Cochran Q test, MR-Egger regression and leave-one-out analyses. Results. 316 instrumental variables (IVs) were included with a total proportion of variance of 7.53% and a mean F-statistic of 94.08. The random-effects model of the inverse-weighted method demonstrated that for every 1-standard deviation decrease in IGF-1, the estimated risk of AIS increases by 37% (OR=0.73, 95% CI 0.62-0.86, P <0.001). The weighted median method provided a consistent estimate of this association (OR=0.74, 95% CI 0.58-0.95, P =0.016). MR-Egger regression demonstrated no evidence of directional pleiotropy (MR‑Egger intercept = −0.00091, P =0.84). While Cochran’s Q statistic demonstrated heterogeneity among IVs for both IVW (Q=345.69, P =0.039) and MR-Egger (Q=345.64, P =0.036), the calculated I² was 12.9%, indicating modest heterogeneity. Leave‑one‑out analysis demonstrated robustness against individual single nucleotide polymorphisms disproportionately influencing the overall association. Conclusion. A decrease of one standard deviation (estimated mean: 22 nmol/L SD:5) in circulating IGF-1 increases the risk of AIS by 37%. The putative causal association between serum IGF-1 levels and AIS warrants further study into the role of IGF-1 in AIS pathogenesis. Patients with short-stature syndromes and other disorders with IGF-1 dysregulation such as growth hormone deficiency should be routinely screened for AIS, and further research is required to assess whether IGF-1 can serve as a serum biomarker for AIS screening at the primary care level.