Causal Relationship Between Sex Hormone Binding Globulin and Obstetrical Disorders: A Two-Sample Bidirectional Mendelian Randomization Study.

INTRODUCTION

Obstetrical disorders critically impact maternal and fetal health. Sex hormone-binding globulin (SHBG) regulates pregnancy maintenance and maternal-infant outcomes through hormonal, metabolic, and inflammatory pathways, yet causal relationships with obstetrical disorders remain unclear. This Mendelian randomization (MR) study examined SHBG's causal effects on 12 obstetrical conditions.

METHODS

Using cis-protein quantitative trait loci (cis-pQTLs) of SHBG as instrumental variables, we conducted MR analyses in FinnGen and UK Biobank (UKBB), followed by meta-analyses. Inverse variance weighting (IVW) was primary method, with sensitivity analyses ensuring robustness.

RESULTS

IVW-MR demonstrated reduced risks with elevated SHBG: gestational diabetes (OR[95%]=0.835[0.785-0.889], P FDR=2.03×10-7), hyperemesis gravidarum (OR[95%]=0.823[0.728-0.931], P FDR=5.94×10-3), gestational hypertension (OR[95%]=0.917[0.852-0.987], P FDR=0.041), and early-pregnancy hemorrhage (OR[95%]=0.853[0.794-0.916], P FDR=6.90×10-5). Meta-analysis confirmed SHBG's causal role in gestational diabetes (P_combined<0.05). COLOC revealed shared loci between SHBG and five disorders: gestational diabetes, hyperemesis, early hemorrhage, preterm delivery, and postpartum hemorrhage.

CONCLUSION

SHBG causally lowers risks of gestational diabetes, hypertension, hyperemesis, miscarriage, and preterm delivery, highlighting its clinical relevance in obstetrical pathophysiology.