Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.
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Reagents and sample hybridization in the replication cohort were provided by the Iowa Institute of Human Genetics Genomics Division (IIHG). We would like to thank Hsiang Wen for sample collection and management for the replication cohort. We would like to thank the study participants in both cohorts for their willingness to participate in the study. This study was supported by the National Institute of Mental Health (NIMH, K01 MH121580 to GRF), the American Foundation for Suicide Prevention (YIG-0-066-20 to GRF), and the Baszucki Research Foundation (GRF). Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School at UTHealth. This study was also supported by an EHSRC Career Enhancement award and an EHSRC Pilot grant (NIH P30 ES005605) awarded to MEG, and an Iowa Neuroscience Institute Research Program of Excellence grant with philanthropy from the Roy J. Carver Charitable Trust. Research reported in this publication for the University of Iowa was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR002537) and the National Institute of Mental Health (NIMH R01MH125838 to VAM and JAW). APD is supported by a 2020 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the American Foundation for Suicide Prevention, or the Baszucki Research Foundation.
The authors declare no competing interests.
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Lima, C.N.C., Kovács, E.H.C., Mirza, S. et al. Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder. Neuropsychopharmacol. 48, 954–962 (2023). https://doi.org/10.1038/s41386-023-01557-9