Genetic Prediction of Osteoporosis by Anti-Müllerian Hormone Levels and Reproductive Factors in Women: A Mendelian Randomization Study

Abstract

Previous observational studies have suggested that anti-Müllerian hormone (AMH) and reproductive factors are linked to reduced bone mineral density (BMD) and an increased risk of osteoporosis (OP) in women. However, related studies are limited, and these traditional observational studies may be subject to residual confounders and reverse causation, while also lacking a more comprehensive observation of various reproductive factors. Univariate and multivariate two-sample Mendelian randomization analyses were conducted to determine the causal associations of AMH levels and six reproductive factors with BMD and OP, using the random-effects inverse-variance weighted method. Heterogeneity was assessed using Cochran's Q-statistic, and sensitivity analyses were performed to identify causal correlations. Age at menarche (AAM) was negatively associated with total body BMD (TB-BMD) in females aged 45-60 and over 60 years, as well as with heel bone mineral density (eBMD). Conversely, age at natural menopause (ANM) was positively associated with TB-BMD in the same age ranges and with eBMD. ANM was only causally associated with self-reported OP and showed no significant correlation with definitively diagnosed OP. Neither AMH level nor other reproductive factors were significantly associated with a genetic predisposition to BMD at any age and OP. Later AAM and earlier ANM are significantly genetically causally associated with decreased BMD but not with OP. AMH levels, length of menstrual cycle, age at first birth, age at last birth, and number of live births, in terms of genetic backgrounds, are not causally related to BMD or OP.

Keywords: Anti-Müllerian hormone; Bone mineral density; Female reproductive factors; Mendelian randomization; Osteoporosis.

Fig. 1

Description of the study design in this Mendelian randomization study and three key assumptions of valid instrumental variables. SNPs single nucleotide polymorphisms

Fig. 2

Univariate Mendelian randomization association of genetic liability to AMH and women’s AMH levels and reproductive factors with OP. OR odds ratio; (I) Represents confounders not eliminated; (II) Represents SNPs associated with physical status such as “height”, “BMI”, “body fat percentage”, and “rheumatoid arthritis” were excluded; (III) Represents SNPs related to lifestyle and social factors such as “smoking”, “alcohol consumption”, “sleep”, “exercise”, and “education” were excluded

Fig. 3

Univariate Mendelian randomization association of genetic liability to AMH, AAM, and ANM with OP. OR odds ratio; CI confidence interval. Significant at the Bonferroni-corrected threshold of p-value < 0.05

Fig. 4

Univariate Mendelian randomization association of genetic liability to AMH with OP after adjusting for the influence of ANM. OR odds ratio; CI confidence interval. Significant at the Bonferroni-corrected threshold of p-value < 0.05

Fig. 5

Multivariate Mendelian randomization association of genetic liability to AAM, LMC, and ANM with OP. OR odds ratio; CI confidence interval. Significant at the Bonferroni-corrected threshold of p-value < 0.05