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A phenome-wide association and Mendelian randomization study for suicide attempt within UK Biobank

Molecular Psychiatry volume 31, pages 1051–1060 (2026)Cite this article

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Abstract

Uncertainties persist in the neurological and behavioral risk factors for suicide attempt (SA) due to a lack of data covering multiple phenotypes. Here, the polygenic risk scores (PRSs) for SA samples within the UK Biobank (N = 40,369) were estimated using non-overlapping Psychiatric Genomics Consortium datasets as a reference. A total of 70 PRS-associated phenotypes encompassing discovered and never-reported phenotypes were identified, thereby facilitating applications in SA identification (area under the curve of 84%). Different with the existing observational studies, the causal effects between brain and SA were explored. Mendelian randomization supported a potential causal effect of right hippocampal gray matter volume on SA, whereas SA had a reverse causal effect on the VI cerebellum. After controlling for the effects of psychiatric disorders, the right hippocampus still had an independent causal effect on SA. These findings provide multi-perspective evidence for early understanding and identification of SA and shed new lights for causal inference between brain and SA.

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Fig. 1: Study design.
Fig. 2: Heatmap of phenotypes significantly associated with SA-PRS.
Fig. 3: Maps of significant associations between SA-PRS and gray matter volumes.
Fig. 4: Bidirectional MR analysis of the causal effect of neuroimaging phenotypes and SA.
Fig. 5: Multivariable MR analysis of the effect of hippocampus on SA after adjusting for six psychiatric disorders.

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Data availability

The summary statistics of SA and 6 psychiatric disorders (i.e., anxiety disorder, ADHD, bipolar disorder, depression, PTSD, and schizophrenia) are available here: : https://pgc.unc.edu/for-researchers/download-results/. The UK Biobank data are available to any bona fide researcher following application: https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.

Code availability

All analyses except the automatic SA detection method were performed using R statistical software with standard functions and toolboxes. The code of the SA detection method is available at the GitHub: https://github.com/Meiyan88/SA-Classification.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82272069, No.12322113, No. 72495122, No. 12288201, and No. 62471214).

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Author notes

  1. These authors contributed equally: Meiyan Huang, Xiaoling Zhang.

Authors and Affiliations

  1. School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, China

    Meiyan Huang, Xiaoling Zhang, Xiumei Chen, Xinyue Zhang & Qianjin Feng

  2. Guangdong Provincial Key Laboratory of Medical Image Processing, Southern Medical University, Guangzhou, 510515, China

    Meiyan Huang & Qianjin Feng

  3. Guangdong Province Engineering Laboratory for Medical Imaging and Diagnostic Technology, Southern Medical University, Guangzhou, 510515, China

    Meiyan Huang & Qianjin Feng

  4. Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (The Affiliated Hospital of Beijing Institute of Technology, Zhuhai Clinical Medical College of Jinan University), Zhuhai, 519000, China

    Xiaoling Zhang

  5. Department of Statistics and Data Science, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Bingxin Zhao

  6. Department of Statistics, Florida State University, Tallahassee, FL, 32306, USA

    Chao Huang

  7. School of Mathematics, Sun Yat-sen University, Guangzhou, 510515, China

    Ting Tian & Chuang Li

  8. State Key Laboratory of Mathematical Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100190, China

    Wenliang Pan

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Contributions

MH: Conceptualization, Methodology, and Writing - Review & Editing. XZ (Xiaoling Zhang): Methodology, Formal analysis, Visualization, and Writing - Original Draft. XC: Formal analysis and Software. XZ (Xinyue Zhang): Investigation and Data Curation. BZ: Writing - Review & Editing. CH: Writing - Review & Editing. TT: Data Curation. CL: Data Curation. QF: Conceptualization, Writing - Review & Editing. WP: Methodology, Supervision, and Writing - Review & Editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Meiyan Huang, Qianjin Feng or Wenliang Pan.

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Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. The UK Biobank has approval from the North West Multi-Centre Research Ethics Committee (https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics, REC reference: 11/NW/0157). All participants gave written informed consent in accordance with the principles of the Declaration of Helsinki. Data acquisition and analyses were conducted under UK Biobank application #68640. This study does not include any identifiable images from human research participants.

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The authors declare no competing interests.

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Huang, M., Zhang, X., Chen, X. et al. A phenome-wide association and Mendelian randomization study for suicide attempt within UK Biobank. Mol Psychiatry 31, 1051–1060 (2026). https://doi.org/10.1038/s41380-025-03214-7

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