An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

doi:10.3389/fgene.2020.00507

. 2020 May 29:11:507.

doi: 10.3389/fgene.2020.00507. eCollection 2020.

An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

Xiaohong Ding^{1

2}, Rong Tang^{1

3}, Jinjin Zhu^{1

3}, Minzhi He^{1

3}, Huasong Huang^{1

3}, Zhenlang Lin¹, Jianghu Zhu^{1

3}

Affiliations

¹ Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² The First Clinical Medical School, Wenzhou Medical University, Wenzhou, China.
³ The Second Clinical Medical School, Wenzhou Medical University, Wenzhou, China.

PMID: 32547598
PMCID: PMC7274172
DOI: 10.3389/fgene.2020.00507

An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

Xiaohong Ding et al. Front Genet. 2020.

. 2020 May 29:11:507.

doi: 10.3389/fgene.2020.00507. eCollection 2020.

Authors

Xiaohong Ding^{1

2}, Rong Tang^{1

3}, Jinjin Zhu^{1

3}, Minzhi He^{1

3}, Huasong Huang^{1

3}, Zhenlang Lin¹, Jianghu Zhu^{1

3}

Affiliations

¹ Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
² The First Clinical Medical School, Wenzhou Medical University, Wenzhou, China.
³ The Second Clinical Medical School, Wenzhou Medical University, Wenzhou, China.

PMID: 32547598
PMCID: PMC7274172
DOI: 10.3389/fgene.2020.00507

Abstract

Objective: Menopause at a young age is associated with many health problems in women, including osteoporosis, depressive symptoms, coronary disease, and stroke. Many traditional observational studies have reported some potential risk factors for early menopause but have drawn different conclusions. This inconsistency can be attributed mainly to unmodified confounding factors. Identifying the factors causally associated with age at menopause is important for early intervention in women with abnormal menopause timing, and for improving the quality of life for postmenopausal women. This study aims to appraise whether the previously reported risk factors are causally associated with early age at natural menopause (ANM) susceptibility.

Methods: We used Mendelian randomization, a statistical method wherein genetic variants are used to determine whether an observational association between a risk factor and an outcome is consistent with a causal effect.

Results: Women with earlier age at menarche (β = 0.34, se = 0.16, p = 0.035), lower education level (β = 1.19, se = 0.41, p = 0.004) and higher body mass index (β = -0.05, se = 0.02, p = 0.027) had greater risk for early ANM. The causal link between early age at menarche and early ANM was replicated using ReproGen consortium data (β = 0.23, se = 0.07, p = 0.001). However, a current smoking habit, one of previously reported risk factors, was less likely to be correlated causally with early ANM, suggesting that previous observational studies may not have sufficiently adjusted for confounders.

Conclusion: Our results help to identify the risk factors of ANM via a genetics approach and future research into the biological mechanism could further help with targeted prevention for early menopause.

Keywords: endocrine; menarche; mendelian randomization; menopause; reproduction.

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Figures

**FIGURE 1**
Schematic diagram for Mendelian randomization analysis. Our study aim to estimate the causal relationship between previously reported risks factors and ANM using SNPs as instrumental variables. SNPs should not be associated with any confounding factors.

See this image and copyright information in PMC

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References

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1. Canavez F. S., Werneck G. L., Parente R. C., Celeste R. K., Faerstein E. (2011). The association between educational level and age at the menopause: a systematic review. Arch. Gynecol. Obstet. 283 83–90. 10.1007/s00404-009-1323-6 - DOI - PubMed

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[1] Ahlborg H. G., Johnell O., Turner C. H., Rannevik G., Karlsson M. K. (2003). Bone loss and bone size after menopause. N. Engl. J. Med. 349 327–334. 10.1056/NEJMoa022464 - DOI - PubMed

[2] Ahlborg H. G., Johnell O., Turner C. H., Rannevik G., Karlsson M. K. (2003). Bone loss and bone size after menopause. N. Engl. J. Med. 349 327–334. 10.1056/NEJMoa022464 - DOI - PubMed

[3] Amrhein V., Greenland S., McShane B. (2019). Scientists rise up against statistical significance. Nature 567 305–307. 10.1038/d41586-019-00857-9 - DOI - PubMed

[4] Amrhein V., Greenland S., McShane B. (2019). Scientists rise up against statistical significance. Nature 567 305–307. 10.1038/d41586-019-00857-9 - DOI - PubMed

[5] Bowden J., Davey Smith G., Burgess S. (2015). Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44 512–525. 10.1093/ije/dyv080 - DOI - PMC - PubMed

[6] Bowden J., Davey Smith G., Burgess S. (2015). Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44 512–525. 10.1093/ije/dyv080 - DOI - PMC - PubMed

[7] Bowden J., Davey Smith G., Haycock P. C., Burgess S. (2016). Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 40 304–314. 10.1002/gepi.21965 - DOI - PMC - PubMed

[8] Bowden J., Davey Smith G., Haycock P. C., Burgess S. (2016). Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 40 304–314. 10.1002/gepi.21965 - DOI - PMC - PubMed

[9] Canavez F. S., Werneck G. L., Parente R. C., Celeste R. K., Faerstein E. (2011). The association between educational level and age at the menopause: a systematic review. Arch. Gynecol. Obstet. 283 83–90. 10.1007/s00404-009-1323-6 - DOI - PubMed

[10] Canavez F. S., Werneck G. L., Parente R. C., Celeste R. K., Faerstein E. (2011). The association between educational level and age at the menopause: a systematic review. Arch. Gynecol. Obstet. 283 83–90. 10.1007/s00404-009-1323-6 - DOI - PubMed

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An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

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An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

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