Causal Relationship between Sex Hormone-Binding Globulin and Risk of Neuroblastoma: A Bidirectional Two-Sample Mendelian Randomization Study

Abstract Background: The causal relationship between sex hormone-binding globulin (SHBG) and neuroblastoma remains unknown. This study aimed to explore the causality between SHBG and the risk of neuroblastoma using bidirectional two-sample Mendelian randomization (MR) study. Methods: Instrumental variables associated with SHBG were obtained from the genome-wide association study (GWAS) of European containing 214,989 females and 185,221 males from the UK Biobank. Summary-level data for neuroblastoma were derived from the IEU OpenGWAS project with 1,627 patients and 3,254 controls. The inverse-variance weighted (IVW) method served as the primary analytic tool. Results: The IVW method revealed a significant positive causal relationship between male SHBG and the risk of neuroblastoma [OR, 2.169; 95% confidence interval (CI), 1.207–3.897; P = 0.010]. Conversely, female SHBG showed no significant causal link with neuroblastoma (IVW OR, 1.004; 95% CI, 0.542–1.860; P = 0.990). No significant reverse causality was detected. Sensitivity analyses validated these findings. Conclusions: Elevated SHBG levels in males, but not in females, can causally increase the risk of neuroblastoma. This gender-specific effect indicates a potential differential role of SHBG in the etiology of neuroblastoma. Further research is needed to elucidate the underlying mechanisms of this gender disparity. Monitoring SHBG levels, especially in males, could be pivotal in neuroblastoma risk assessment and management. Impact: This study highlights a novel gender-specific aspect in the risk of neuroblastoma, emphasizing the potential role of male SHBG levels in neuroblastoma incidence, and sets the stage for targeted preventative strategies and further investigation into gender-based biological mechanisms.