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BMA-based Mendelian randomization identifies blood metabolites as causal candidates in pregnancy-induced hypertension

Hypertension Research volume 47, pages 2549–2560 (2024)Cite this article

A Comment to this article was published on 16 August 2024

Abstract

Pregnancy-induced hypertension (PIH), a prominent determinant of maternal mortality and morbidity worldwide, is hindered by the absence of efficacious biomarkers for early diagnosis, contributing to suboptimal outcomes. Here, we explored potential causal relationships between blood metabolites and the risk of PIH using Mendelian randomization (MR). We employed a two-sample univariable MR approach to empirically estimate the causal relationships between 249 circulating metabolites and PIH. Inverse variance weighted, MR-egger, weight median, simple mode, and weighted mode methods were used for causal estimates. The exposure-to-outcome directionality was confirmed with the MR Steiger test. The Bayesian model averaging MR (MR-BMA) method was applied to detect the predominant causal metabolic traits with alignment for pleiotropy effects. In the primary analysis, analyzing 249 metabolites, we identified 25 causally linked to PIH, including 11 lipid-related traits and 6 associated with fatty acid (un)saturation. Importantly, MR-BMA analyses corroborated the total concentration of branched-chain amino acids(total-BCAA) to be the highest rank causal metabolite, followed by leucine (Leu), phospholipids to total lipids ratio in medium LDL (M-LDL-PL-pct), and Val (all P < 0.05). The directionality of causality predicted by univariable MR and MR-BMA for these metabolites remained consistent. This study highlights the causal connection between metabolites and PIH risk. It highlighted BCAAs as the strongest causal candidates warranting further investigation. Since PIH typically occurs in the second and third trimesters, extending these findings could inform earlier strategies to reduce its risk.

Directed acyclic graph of the MR framework investigating the causal relationship between metabolites and PIH. MR: Mendelian randomization; GIVs: genetic instrument variables; SNPs: single-nucleotide polymorphism; IVW: inverse variance weighted; WM: weighted median; PIH: pregnancy-induced hypertension; SM: significant metabolite; MR-BMA: Bayesian model averaging MR.

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Funding

This work was supported by Shandong Provincial Natural Science Foundation, China (ZR2023QH345).

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Author notes

  1. These authors contributed equally: Jun Guo, Xiaofei Zheng.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, Anhui, China

    Jun Guo, Xue Du & Likui Lu

  2. Department of Radiology, The First Affiliate Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, China

    Jun Guo

  3. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Xiaofei Zheng

  4. Department of gynaecology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China

    Weisheng Li

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  1. Jun Guo
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Contributions

JG and XFZ: Study conception, design, Analyses and Draft; XD: Analyses; WSL and LKL: Supervision and validation. All authors read and approved the final manuscript.

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Correspondence to Weisheng Li or Likui Lu.

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The datasets utilized in this study were obtained from the IEU Open GWAS database (https://gwas.mrcieu.ac.uk/). These public databases permit researchers to access and analyze public datasets for scientific research, rendering ethics approval unnecessary.

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Guo, J., Zheng, X., Du, X. et al. BMA-based Mendelian randomization identifies blood metabolites as causal candidates in pregnancy-induced hypertension. Hypertens Res 47, 2549–2560 (2024). https://doi.org/10.1038/s41440-024-01787-4

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