Age at natural menopause and blood pressure traits: Mendelian randomization study

Zayne M. Roa-Díaz, Eralda Asllanaj, Hasnat A. Amin, Lyda Z. Rojas, Jana Nano, Mohammad Arfan Ikram, Fotios Drenos, Oscar H. Franco, Raha Pazoki, Pedro Marques-Vidal, Trudy Voortman, Taulant Muka*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = −1.31, 95% CI −2.43; −0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.

Original languageEnglish
Article number4299
Number of pages13
JournalJournal of Clinical Medicine
Issue number19
Publication statusPublished - 22 Sep 2021

Bibliographical note

Funding Information:
The CoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). Zayne M. Roa-Díaz have received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 801076, through the SSPH+Global Ph.D. Fellowship Program in Public Health Sciences (GlobalP3HS) of the Swiss School of Public Health.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


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