Abstract
Chronic pain represents heritable conditions linked to suicide death. It has been suggested that a shared genetic predisposition may contribute to this relationship, but there has not yet been a comprehensive assessment of genetic and clinical overlaps of different types of chronic pain with suicide death. Here, we integrated whole-genome sequencing and electronic health records from 986 unrelated individuals of European ancestry who died by suicide in the Utah Suicide Mortality Research Study and 415 ancestrally-matched population controls selected for absence of disease. Polygenic scores (PGSs) for seven distinct types of chronic pain were calculated and tested in the suicide cohort. We observed significant positive associations of PGSs for multisite chronic pain (PGSMCP) and chronic widespread pain (PGSCWP) with suicide mortality. Sex-stratified analyses showed elevations in both males and females. Pain diagnosis-stratified analyses revealed associations with suicide death regardless of chronic pain diagnoses. Follow-up tests of PGSs for more specific pain conditions showed additional associations with suicide death for: 1) monoarticular arthritis, 2) back pain, and 3) chronic inflammatory demyelinating polyneuropathy across all suicide death individuals, and 4) irritable bowel syndrome within males only. In a multiple logistic regression test of all chronic pain PGSs associating suicide death status, four types of pain remained uniquely associated with suicide death, highlighting distinct subgroups within suicide death: some attributed to MCP and CWP, and others associated with monoarticular arthritis or chronic inflammatory demyelinating polyneuropathy. This cohort study reports associations between suicide death and PGSs from various pain conditions, regardless of sex or chronic pain diagnosis, suggesting that combining genetic and clinical risk factors may better identify genetic overlap, causal directions, and/or specific gene pathways.
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Data availability
Publicly available GWAS datasets investigated in this study are available from the following sources. Multisite chronic pain: https://www.ebi.ac.uk/gwas/publications/31194737. Chronic widespread pain: https://zenodo.org/records/4459546. Monoarticular arthritis: https://www.ebi.ac.uk/gwas/publications/34737426. Back pain: https://zenodo.org/records/1319332, Chronic inflammatory demyelinating polyneuropathy: https://www.ebi.ac.uk/gwas/publications/34737426. Irritable bowel syndrome: https://www.ebi.ac.uk/gwas/publications/34741163, and Knee pain: https://www.ebi.ac.uk/gwas/publications/31482140. Additional data from this study is available from the authors upon request.
Code availability
PRSice-2: https://choishingwan.github.io/PRSice/; PRS-CS: https://github.com/getian107/PRScs; LDSC: https://github.com/bulik/ldsc; PLINK v1.9: https://www.cog-genomics.org/plink/1.9.
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Funding
This work was supported by the National Institutes of Health (R01MH122412, R01MH123489, R01MH123619, R01ES032028); the American Foundation for Suicide Prevention (VW, HC: BSG-1-005-18), the Brain & Behavior Research Foundation-NARSAD (ED, grant number 28132; AS grant number 28686; EM grant number 31248); and the Clark Tanner Foundation (HC, AS, EM, AB). Cellular Translational Research Core Services at the University of Utah are supported by NIH CTSA UM1 TR004409. Partial support for all datasets housed within the Utah Population Data Base is provided by the Huntsman Cancer Institute (HCI), http://www.huntsmancancer.org/, and the HCI Cancer Center Support grant, P30CA42014 from the National Cancer Institute. Whole-genome sequencing of suicide deaths was supported in part by a donation from the Huntsman Mental Health Institute. Research was supported by NCRR grant “Sharing statewide health data for genetic research” R01RR021746 with additional support from the Utah Department of Health and Human Services and the University of Utah. We thank the University of Utah Pedigree and Population Resource and the University of Utah Health Enterprise Data Warehouse for establishing the Master Subject Index between the Utah Population Database and the University of Utah Health Sciences Center. We additionally thank our colleagues at Intermountain Health for working with Utah Population Database staff in linkage and subsequent de-identification of IH health records data.
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SH, AD, and HC conceptualized and designed this study. SH, ED, EM, AS, DC, KE, AB, BK, HC, and AD contributed to analysis and interpretation of EHR and genomics data. LB, DC, DL, DT, EF were involved in data preparation. QL, VW, HC, and AD generated whole-genome sequencing data. All of the funding and work needed to generate whole-genome sequencing data includes only QL, FW, and HC. ZY and DC contributed to integration of clinical and demographic data with de-identification. WC, MS, and HC collected biosamples for suicide death. ED and AO were involved in defining suicide cases with chronic pain conditions and interpreting results in the context of chronic pain. SH, ED, EM, HC, and AD prepared the first draft of the manuscript. HC and AD supervised this study. All authors contributed to completing the manuscript by reading and revising it. All authors approved the final manuscript.
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Qingqin S. Li is an employee of Janssen Research and Development. All other authors declare no conflicts of interest.
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All methods were performed in accordance with the relevant guidelines and regulations. Ethical approval for this study is received annually from Institutional Review Boards of the University of Utah, Intermountain Health, and the Utah Department of Health and Human Services, and informed consent was obtained from all subjects prior to study participation.
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Han, S., DiBlasi, E., Monson, E.T. et al. Genetic risk of chronic pain conditions associated with risk of suicide death through an integrative analysis of EHR and genomics data. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03861-6
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DOI: https://doi.org/10.1038/s41398-026-03861-6


