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Cross-phenotype relationship between opioid use disorder and suicide attempts: new evidence from polygenic association and Mendelian randomization analyses

Molecular Psychiatry volume 28, pages 2913–2921 (2023)Cite this article

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A Correction to this article was published on 12 December 2023

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Abstract

Clinical epidemiological studies have found high co-occurrence between suicide attempts (SA) and opioid use disorder (OUD). However, the patterns of correlation and causation between them are still not clear due to psychiatric confounding. To investigate their cross-phenotype relationship, we utilized raw phenotypes and genotypes from >150,000 UK Biobank samples, and genome-wide association summary statistics from >600,000 individuals with European ancestry. Pairwise association and a potential bidirectional relationship between OUD and SA were evaluated with and without controlling for major psychiatric disease status (e.g., schizophrenia, major depressive disorder, and alcohol use disorder). Multiple statistical and genetics tools were used to perform epidemiological association, genetic correlation, polygenic risk score prediction, and Mendelian randomizations (MR) analyses. Strong associations between OUD and SA were observed at both the phenotypic level (overall samples [OR = 2.94, P = 1.59 ×10−14]; non-psychiatric subgroup [OR = 2.15, P = 1.07 ×10−3]) and the genetic level (genetic correlation rg = 0.38 and 0.5 with or without conditioning on psychiatric traits, respectively). Consistently, increasing polygenic susceptibility to SA is associated with increasing risk of OUD (OR = 1.08, false discovery rate [FDR] =1.71 ×10−3), and similarly, increasing polygenic susceptibility to OUD is associated with increasing risk of SA (OR = 1.09, FDR = 1.73 ×10−6). However, these polygenic associations were much attenuated after controlling for comorbid psychiatric diseases. A combination of MR analyses suggested a possible causal association from genetic liability for SA to OUD risk (2-sample univariable MR: OR = 1.14, P = 0.001; multivariable MR: OR = 1.08, P = 0.001). This study provided new genetic evidence to explain the observed OUD-SA comorbidity. Future prevention strategies for each phenotype needs to take into consideration of screening for the other one.

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Fig. 1: Bi-directional two-sample Mendelian randomization results between OUD and SA.

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Data availability

All analyses were conducted using publicly available data. Complete genetic datasets for every analysis included in this study are available in the Supplement. The individual-level data publicly available summary-level data is available by application at https://www.ukbiobank.ac.uk/. For summary-level data, SA was accessed through ISGC dropbox link (upon request) or iPSYCH data repository (https://ipsych.dk/en/research/downloads). OUD and AUD were accessed through NCBI dbGaP for MVP (phs001672.v6.p1) [39]. MDD, BD, SCZ, ANX and PTSD were accessed at https://www.med.unc.edu/pgc/results-and-downloads/ and through MR Base at https://www.mrbase.org/. Code Availability: analyses were performed with standard tools, including GCTA (v 1.93.2), LDSC (v 1.0.1), and multiple R Packages (TwoSampleMR [v 0.5.5], MRPRESSO [v 1.0], MVMR [v 0.2], and MendelianRandomization [v 0.6.0]). The analysis code in R is available on request, and all data displayed in the figures are available in the Supplement. Supplementary information is available at MP’s website.

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Acknowledgements

This research was made possible by previous studies from PGC, MVP, iPSYCH, the developers of the MRC-IEU UK Biobank, and researchers from ISGC (especially Dr. Niamh Mullins), who provided the latest European-ancestry statistics on SA. We acknowledge their contributing studies and the participants in those studies, without whom this effort would not be possible. We thank Dr. Lisa Matero for providing insights on clinical implication of this genetic study.

Funding

This study was financially supported by the National Nature Science Foundation of China (Grant NO.82171499 to QW), Science and Technology Project of Sichuan Province (2023YFS0030 to QW) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology-China Depression Cohort Study (2021ZD0200700 to QW). BKA is supported by NIH Award (OT2OD026550). HG is supported by Mentored Scientist Grant in Henry Ford Health (A20067). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Yunqi Huang & Qiang Wang

  2. West China Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Yunqi Huang & Qiang Wang

  3. Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, Sichuan, China

    Yunqi Huang & Qiang Wang

  4. Center for Health Policy and Health Services Research, Henry Ford Health, Detroit, MI, USA

    Dongru Chen, Brian K. Ahmedani & Hongsheng Gui

  5. Department of Public Health Sciences, Henry Ford Health, Detroit, MI, USA

    Albert M. Levin

  6. Behavioral Health Services and Psychiatry Research, Henry Ford Health, Detroit, MI, USA

    Brian K. Ahmedani, Cathrine Frank & Hongsheng Gui

  7. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China

    Miaoxin Li

  8. Department of Psychiatry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China

    Pak-Chung Sham

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Contributions

QW and HG have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. Concept and design: All authors. Acquisition, analysis, or interpretation of data: YH, DC, QW, HG. Drafting of the manuscript: YH, QW, HG. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: YH, DC, ML, QW, HG. Obtained funding: QW, HG. Administrative, technical, or material support: QW, HG. Supervision: QW, HG, PCS.

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Correspondence to Qiang Wang or Hongsheng Gui.

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The original online version of this article was revised: In this article the statement in the Funding information section was incorrectly given as ‘This study was financially supported by the National Nature Science Foundation of China (Grant No. 81771446 to QW)’ and should have read ‘This study was financially supported by the National Nature Science Foundation of China (Grant No. 82171499 to QW and No. 81771446 to QW)’.

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Huang, Y., Chen, D., Levin, A.M. et al. Cross-phenotype relationship between opioid use disorder and suicide attempts: new evidence from polygenic association and Mendelian randomization analyses. Mol Psychiatry 28, 2913–2921 (2023). https://doi.org/10.1038/s41380-023-02124-w

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  • DOI: https://doi.org/10.1038/s41380-023-02124-w

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