Journal Article Annotations
2025, 3rd Quarter

Aging

Annotations by Zachary Harvanek, MD, PhD
September, 2025

DNA methylation patterns and epigenetic aging associated with suicide attempts in bipolar disorder.

PUBLICATION #1 — Aging

DNA methylation patterns and epigenetic aging associated with suicide attempts in bipolar disorder.

Marina Mitjans, Miriam Acosta-Díez, Anna Giménez-Palomo, Marina Zafrilla-López, Pilar A Saiz, Carme Barrot-Feixat, Esther Jiménez, Sergi Papiol, Javier Defez, Alexandre Xifró-Collsamata, Marisa Ortega-Sánchez, Victoria Ruiz, Patrícia Gavín, María Paz García-Portilla, Leticia González-Blanco, Julio Bobes, Thomas G Schulze, Eduard Vieta, Antoni Benabarre, Bárbara Arias.

Abstract: J Affect Disord. 2025 Aug 24:392:120118. doi: 10.1016/j.jad.2025.120118. Online ahead of print.

Background:
Suicidal thoughts and behaviors (STBs) are a public health issue highly prevalent in bipolar disorder (BD). Multiple factors contribute to STBs, and new evidence highlights the significant role of epigenetics, specifically DNA methylation (DNAm). Additionally, recent studies found accelerated epigenetic aging (EA) in both BD and STBs. This study aimed to detect epigenetic risk factors for STBs, particularly for suicide attempts (SAs), comparing DNAm patterns and EA between BD patients with (BD/SA) and without (BD/non-SA) a history of SAs. Moreover, EA was calculated to explore age acceleration (AgeAccel) in the BD/SA group.

Methods:
Genome-wide DNAm patterns of blood samples from 46 BD/SA and 32 BD/non-SA were assessed using Infinium HumanMethylationEPIC v1.0 BeadChip (Illumina). Differentially methylated positions (DMPs) and regions (DMRs) were compared between groups. Gene network analysis was performed using genes mapped to DMPs and DMRs. Lastly, EA from different epigenetic clocks was estimated and compared between groups.

Results:
We identified 18 DMPs and 2 DMRs (adjusted p-value < 0.05) between BD/SA and BD/non-SA. Among the 18 genes mapped to DMPs and DMRs, the MAD1L1 gene was previously associated with severe SAs. Trends of AgeAccel using the GrimAge and GrimAge2 clocks (p-value ≤ 0.022; adjusted p-value > 0.05) were found in BD/SA.

Limitations:
Relatively small sample size, cross-sectional design, and use of peripheral blood.

Conclusions:
Our findings highlight the importance of considering epigenetic markers when studying SAs in mental disorders. These results may contribute to a better understanding of the biological basis of SAs in BD, which could ultimately help identify at-risk individuals for SAs.

Annotation

The finding:
In this study of patients with bipolar disorder (BD), the authors examine whether there are differences in DNA methylation patterns between individuals with a history of suicide attempts (BD/SA; n = 46) and those without (BD/non-SA; n = 32). The authors identified 18 differentially methylated positions (DMPs) and 2 differentially methylated regions (DMRs) between groups. One of these DMPs was in a gene previously implicated in suicidal behaviors in bipolar disorder (MAD1L1). Gene network analysis suggested enrichment in pathways related to cancer, gastrointestinal, and hepatic disease. The authors found that two epigenetic clocks, GrimAge and GrimAgeV2, showed nominally significant acceleration in individuals with suicide attempts (p = 0.008 and p = 0.022, respectively), which did not survive correction for multiple testing.

Strength and weaknesses:
This study has some strengths, including rigorous quality control methodology, the use of multiple comparisons correction, and the integration of gene network analyses to better contextualize their findings. However, this study has a relatively small sample size (total n = 78), with a cross-sectional design and lacks a healthy control sample, relying on differences between those with/without prior suicide attempts for inference. While the sample is generally well-matched, there is a notable difference between those with/without prior attempts in anti-depressant use (more common in those with a prior attempt, p = 0.006), which could confound the results and is not controlled for in the regression analyses.

Relevance:
This study provides preliminary evidence that DNA methylation and epigenetic aging may be associated with suicide attempts in patients with bipolar disorder. While these findings did not withstand multiple testing correction, they align with prior work suggesting biological aging processes may contribute to the elevated morbidity and mortality observed in BD, especially among those with suicidal behavior. If replicated in larger, longitudinal cohorts, peripheral epigenetic markers could inform risk stratification and early intervention strategies for suicide prevention in BD.