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Bidirectional causal associations between plasma metabolites and bipolar disorder

Molecular Psychiatry volume 30, pages 3998–4005 (2025)Cite this article

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Abstract

Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84–0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87–0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05–1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD.

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Fig. 1: Flowchart of the study.
Fig. 2: Forest plot of causal effects of plasma metabolites on BD (FDR < 0.05).
Fig. 3: Forest plot of causal effects of BD on plasma metabolites (P < 0.05).
Fig. 4: Druggability of plasma metabolites with a causal effect on BD.
Fig. 5: One colocalized region between metabolites and BD.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

The authors thank all investigators and participants from the groups for sharing these data.

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Authors and Affiliations

  1. Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China

    Qian Zhao & Fuquan Zhang

  2. School of Systems Biology, George Mason University, Fairfax, 22030, USA

    Ancha Baranova & Hongbao Cao

  3. Research Centre for Medical Genetics, Moscow, 115478, Russia

    Ancha Baranova

  4. Department of Radiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China

    Dongming Liu

  5. Institute of Neuropsychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China

    Fuquan Zhang

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Contributions

QZ: Writing – Original Draft; Writing – Review & Editing; Visualization. AB, DL, and HC: Writing – Review & Editing. FZ: Conceptualization; Formal Analysis; Supervision. All authors contributed to the revision of the manuscript. All authors approved the final version. FZ is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Fuquan Zhang.

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This study adheres to the STROBE-MR guidelines. The genome-wide association study cohorts used in this research received ethical approval, and informed consents were obtained as documented in the original studies from which these datasets were derived.

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Zhao, Q., Baranova, A., Liu, D. et al. Bidirectional causal associations between plasma metabolites and bipolar disorder. Mol Psychiatry 30, 3998–4005 (2025). https://doi.org/10.1038/s41380-025-02977-3

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