Mendelian randomization identifies age at menarche as an independent causal effect factor for gestational diabetes mellitus

Abstract

Aims: The relationship between age at menarche (AAM) and gestational diabetes mellitus (GDM) risk is still inconclusive. This Mendelian randomization (MR) analysis was used to assess systematically the causal relationship between AAM and GDM risk in human beings.

Materials and methods: Single-nucleotide polymorphisms associated with AAM, oestradiol levels, sex hormone-binding globulin (SHBG) levels and bioavailable testosterone (BioT) levels were screened via the genome-wide association study enrolling individuals of European descent. Summary-level data for GDM (123 579 individuals) were extracted from the UK Biobank. An inverse-variance-weighted method was used for the primary MR analysis. Sensitivity analyses were examined via MR-Egger regression, heterogeneity tests, pleiotropy tests and leave-one-out tests. The directionality that exposure causes the outcome was verified using the MR-Steiger test.

Results: Genetically predicted early AAM was found to have a causal positive association with a higher risk of GDM (odds ratio = 0.798, 95% confidence interval = 0.649-0.980, p = .031). In the multivariable MR analysis adjusted for oestradiol, SHBG and BioT levels, the causal association between AAM and GDM risk remained (odds ratio = 0.651, 95% confidence interval = 0.481-0.881, p = .006). A 1-SD increase in SHBG or BioT levels was significantly associated with a 41.4% decrease or 20.8% increase in the overall GDM risk (p = 3.71E-05 and .040), respectively. However, after controlling for AAM, oestradiol levels and BioT levels by multivariable MR analysis, there was no direct causal effect of SHBG levels on GDM risk (p = .084). Similarly, after adjusting for AAM, oestradiol levels and SHBG levels by multivariable MR analysis, there was no direct causal effect of BioT levels on the risk of GDM (p = .533). In addition, no direct causal association was identified between oestradiol levels and GDM risk in univariable MR analysis or multivariable MR analysis.

Conclusion: Genetic variants predisposing individuals to early AAM were independently associated with higher GDM risk. Further research is required to understand the mechanisms underlying this putative causative association. In addition, AAM may be helpful in clinical practice to identify women at risk for GDM; pregnant women who are young for menarche may need to take precautions before GDM develops.

Keywords: Mendelian randomization; age at menarche; bioavailable testosterone; gestational diabetes mellitus; oestradiol; sex hormone-binding globulin.