Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder

Abstract

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.

Investigating the relationship between DNA methylation, genetic variation, and suicide attempt in bipolar disorder

“…Other studies have identified immune abnormalities associated with suicidal behavior, including altered inflammatory markers and links to autoimmune disorders [39–41]. Our work is also consistent with a recent epigenetic study focused on suicide attempt in BD that found altered DNA methylation in immune-related genes [9]. It is difficult to separate whether these DNA methylation changes are a causal factor of suicide or a consequence of the suicide attempt.…”

“…The Iowa Neuroscience Institute’s Bipolar Disorder Research Program of Excellence (BD-RPOE) recruited participants, after University of Iowa Institutional Review Board approval, for this study as previously described [9, 11, 20–28]. Written informed consent was provided by all participants and most also provided a blood sample for epi/genetic analyses.…”

“…Individuals with BD and a high suicidality score showed hypermethylation at Nucleoporin 133 ( NUP133 ), hypomethylation at MAGUK P55 Scaffold Protein 4 ( MPP4 ), and hypomethylation at TBC1 Domain Family Member 16 ( TBC1D16 ) [8]. A study of those with a history of suicide attempts and BD found several differentially methylated CpG sites and regions with the strongest findings located in C-X-C Motif Chemokine Ligand 8 ( CXCL8 ) and Tripartite Motif Containing 40 ( TRIM40 ), both inflammatory genes [9]. A targeted sequencing study focused on suicide death investigated over 3.7 million CpG sites and reported hypomethylation at Rho Guanine Nucleotide Exchange Factor 38 ( ARHGEF38) [10].…”