Mendelian randomization identifies age at menarche as an independent causal factor for GDM risk

The relationship between age at menarche (AAM) and the risk of gestational diabetes mellitus (GDM) remains unclear. The aim of a Mendelian randomization (MR) analysis was to systematically evaluate the causal relationship between AAM and GDM risk.

This study entailed a genome-wide association study involving individuals of European descent to identify single-nucleotide polymorphisms linked to AAM, estradiol levels, sex hormone-binding globulin (SHBG) levels, and bioavailable testosterone (BioT) levels. Summary-level data for GDM, involving 123,579 individuals, were obtained from the UK Biobank. The primary MR analysis utilized an inverse-variance-weighted method. The MR-Steiger test was used to verify the directionality of exposure causing the outcome.

It was found that genetically predicted early AAM showed a causal positive association with an increased risk of GDM. In a multivariable MR analysis adjusted for estradiol, SHBG, and BioT levels, the association between AAM and GDM risk remained significant. A 1-SD increase in SHBG or BioT levels was significantly linked to a 41.4% decrease or 20.8% increase in GDM risk, respectively. However, after adjusting for AAM, estradiol, and BioT levels, no direct causal effect of SHBG on GDM risk was observed. Similarly, no direct causal effect of BioT on GDM risk was found after adjusting for AAM, estradiol, and SHBG levels. Further, there was no direct causal association between estradiol levels and GDM risk in either univariable or multivariable MR analysis.

The results suggested that genetic predisposition to early AAM is independently associated with a higher GDM risk. Further research is needed to understand the mechanisms behind this causal relationship. Clinically, AAM could help identify women at risk for GDM – suggesting that those with early menarche should take precautions to prevent GDM.

Source: Lu L, Wan B, Sun M. Diabetes, Obesity and Metabolism. 2023 Jan;25(1):248-60.