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.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort ofn = 84 adults with BD with a history of SA (BD/SA),n = 79 adults with BD without history of SA (BD/non-SA), andn = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort ofn = 48 BD/SA andn = 47 BD/non-SA, fold changes at the discovery cohort’s significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8–93.8%) and 82.1% (CI = 73.6–90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort’s significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Background/Objectives: Parity, the number of times a woman carries a pregnancy to viability, has been linked to long-term maternal health outcomes. The mechanisms linking parity to health outcomes are poorly understood but may reflect influences of pregnancy on the maternal epigenome. Methods: This study examines the relationship between parity and DNA methylation (DNAm) during pregnancy using data from three cohorts: the Norwegian Mother, Father and Child Cohort Study (MoBa), the Atlanta African American Maternal-Child (AAAMC) cohort, and the Isle of Wight (IOW) Birth Cohort. Results: An epigenome-wide association study (EWAS) in MoBa identified 5374 cytosine–phosphate–guanine sites (CpGs) that were statistically significantly associated with parity, of which 69% were positively and 31% negatively correlated. Replication analyses confirmed 3491 CpGs in at least one cohort, and 93 CpGs in both AAAMC and IOW. Gene enrichment analysis revealed significant involvement of developmental and signaling pathways, including calcium signaling and neuroactive ligand–receptor interaction. Additionally, 584 differentially methylated regions (DMRs) were detected, with 90% overlapping individual parity-related CpGs. Conclusions: These findings suggest that parity influences epigenetic patterns, potentially affecting biological processes and molecular functions relevant to maternal health later in life.

Associations have been seen between suicide and differential DNA methylation, with one study showing significant hypomethylation of ARHGEF38 in individuals with bipolar disorder who died by suicide. Our objective was to explore ARHGEF38 methylation in individuals with bipolar disorder and a history of suicide attempt. With pyrosequencing, we looked at the previously identified region of interest in ARHGEF38. We investigated the methylation levels of three CpG sites in 47 individuals with bipolar disorder and a history of suicide attempt, 47 individuals with bipolar disorder without a history of suicide attempt, and 47 non-bipolar disorder controls. None of the CpG sites measured had an association between groups, although there were distinct clusters of differential methylation in each group. Applying genotypes of SNPs found in the region of interest, rs2121558 and rs1447093, these clusters showed stepwise methylation at each CpG site, regardless of phenotype. In this small sample size study, differential methylation in ARHGEF38 was not associated with history of suicide attempt, failing to replicate findings from a related outcome, suicide death. However, we did provide evidence of SNP and DNA methylation interplay in this region. This highlights the relevance of considering genetics when interrogating epigenetic mechanisms.