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.
Institute of Child Development, University of Minnesota, 55455, Minneapolis, MN, USA.
Transl Psychiatry. 2024 Jan 31;14(1):70. doi: 10.1038/s41398-024-02760-y.
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 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.
自杀未遂（SA）的风险在双相情感障碍（BD）患者中升高，DNA 甲基化模式可能作为 SA 的潜在生物标志物。我们进行了全基因组关联研究（EWAS），以研究与 BD 和 SA 相关的血液 DNA 甲基化。在一个包含 84 名有 SA 病史的 BD 患者（BD/SA）、79 名无 SA 病史的 BD 患者（BD/non-SA）和 76 名非精神病对照（CON）的发现队列中，测量了超过 700,000 个位置的 DNA 甲基化。BD/SA 与 BD/non-SA 之间存在 6 个差异甲基化位置（DMP）和 7 个差异甲基化区域（DMR），涉及多个免疫相关基因。当 BD/SA 和 BD/non-SA 分别与 CON 比较时，没有全基因组显著差异，且模式表明，区分 BD/SA 与 BD/non-SA 的表观遗传学差异不会区分 BD/non-SA 与 CON。BD/SA 与 BD/non-SA 对比的加权基因共甲基化网络分析和性状富集分析进一步证实了免疫系统的参与，而基因本体分析则表明钙信号传导的作用。在一个包含 48 名 BD/SA 和 47 名 BD/non-SA 的独立复制队列中，发现队列中显著位点的折叠变化在两个队列中表现出中等相关性，并且方向一致。在两个队列中，当将显著 CpG 位点的甲基化和临床访谈信息相结合时，BD 患者中 SA 病史的分类准确性最高，在发现队列和复制队列中，基于这些信息的表观遗传学-临床分类器的 AUC 分别为 88.8%（CI=83.8-93.8%）和 82.1%（CI=73.6-90.5%）。我们的研究结果为免疫系统在 SA 和 BD 中的作用提供了新的见解，也表明整合来自多个分析层次的信息有望提高对 BD 成年患者 SA 风险的评估。
