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Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach

Neuropsychopharmacology (2024)Cite this article

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Abstract

Bipolar disorder (BD) and schizophrenia (SZ) are associated with higher odds of suicide attempt (SA). In this study, we aimed to explore the effect of BD and SZ genetic liabilities on SA, also considering the contribution of behavioral traits, socioeconomic factors, and substance use disorders. Leveraging large-scale genome-wide association data from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (UKB), we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the putative causal effect of BD (41,917 cases, 371,549 controls) and SZ (53,386 cases, 77,258 controls) on SA (26,590 cases, 492,022 controls). Then, we assessed the putative causal effect of BD and SZ on behavioral traits, socioeconomic factors, and substance use disorders. Considering the associations identified, we evaluated the direct causal effect of behavioral traits, socioeconomic factors, and substance use disorders on SA using a multivariable MR approach. The genetic liabilities to BD and SZ were associated with higher odds of SA (BD odds ratio (OR) = 1.24, p = 3.88 × 10−12; SZ OR = 1.09, p = 2.44 × 10-20). However, while the effect of mental distress (OR = 1.17, p = 1.02 × 10-4) and risk-taking (OR = 1.52, p = 0.028) on SA was independent of SZ genetic liability, the BD-SA relationship appeared to account for the effect of these risk factors. Similarly, the association with loneliness on SA was null after accounting for the effect of SZ genetic liability. These findings highlight the complex interplay between genetic risk of psychiatric disorders and behavioral traits in the context of SA, suggesting the need for a comprehensive mental health assessment for high-risk individuals.

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Fig. 1: Study overview.
Fig. 2: Effect of the genetic liability to schizophrenia and bipolar disorder on suicide attempt.
Fig. 3: Consistency across Mendelian Randomization (MR) methods and data sources (i.e., full-scale and non-overlapping samples) considering associations of bipolar disorder and schizophrenia genetic liabilities with behavioral traits, socioeconomic factors and substance use disorders.
Fig. 4: Consistency across Mendelian Randomization (MR) methods and data sources (i.e., full-scale and non-overlapping samples) considering associations of genetic liability for behavioral traits, socioeconomic factors and substance use disorders with suicide-attempt identified as Bonferroni significant in the MRlap analysis.
Fig. 5: Multivariable Mendelian randomization.

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Data availability

All results used to make conclusions discussed in this study are provided as Supplementary Material. All GWAS data are publicly available on their respective websites. Pan-UK Biobank, https://pan.ukbb.broadinstitute.org/downloads. Psychiatric Genomics Consortium, https://pgc.unc.edu/for-researchers/download-results/. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, https://ipsych.dk/en/research/downloads. GWAS & Sequencing Consortium of Alcohol and Nicotine use, https://genome.psych.umn.edu/index.php/GSCAN#GSCAN_GWAS_Phase_2.

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Acknowledgements

The authors thank the participants and the investigators involved in the Psychiatric Genomics Consortium and the UK Biobank.

Funding

Funding

This study was funded by the American Foundation for Suicide Prevention (PDF-1-022-21). The authors also acknowledge support from the National Institutes of Health (R33 DA047527, RF1 MH132337), and One Mind. 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. Department of Psychiatry, Yale School of Medicine, West Haven, CT, 06516, USA

    Brenda Cabrera-Mendoza, Necla Aydin & Renato Polimanti

  2. VA CT Healthcare System, West Haven, CT, 06516, USA

    Brenda Cabrera-Mendoza & Renato Polimanti

  3. Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Necla Aydin

  4. Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, (UTHealth), 77054, Houston, TX, USA

    Gabriel R. Fries & Consuelo Walss-Bass

  5. Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, 77054, Houston, TX, USA

    Gabriel R. Fries & Consuelo Walss-Bass

  6. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA

    Anna R. Docherty

  7. Huntsman Mental Health Institute, Salt Lake City, UT, USA

    Anna R. Docherty

  8. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Anna R. Docherty

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Contributions

BCM and RP conceived and designed the study. BCM and NA performed the analysis. GRF, ARD, CWB contributed to the interpretation of the results. BCM and RP drafted the manuscript. All authors edited or approved the final manuscript and are in agreement to be accountable for its contents.

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Correspondence to Brenda Cabrera-Mendoza.

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RP received a research grant from Alkermes and is paid for his editorial work on the journal Complex Psychiatry. The other authors declare no competing interests.

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Cabrera-Mendoza, B., Aydin, N., Fries, G.R. et al. Estimating the direct effects of the genetic liabilities to bipolar disorder, schizophrenia, and behavioral traits on suicide attempt using a multivariable Mendelian randomization approach. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01833-2

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  • DOI: https://doi.org/10.1038/s41386-024-01833-2

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