Altered expression of histamine signalling genes in postmortem brain samples of individuals who died by suicide: A candidate gene meta-analysis of bulk transcriptomic data

Abstract Suicide remains a significant global health issue, yet its underlying neurobiological mechanisms are not fully understood. Emerging evidence suggests histamine signalling may play a role. Nevertheless, studies directly assessing histamine signalling alterations in the context of suicide have been scant and with inconsistent findings. Here, we conducted a meta-analysis of transcriptomic data from post-mortem brain samples available via the GEO database, examining genes central to histamine signalling pathways - histamine receptors 1–4 (HRH1, HRH2, HRH3, HRH4), the main enzyme involved in histamine synthesis L-histidine decarboxylase (HDC), and the two main enzymes involved in histamine catabolism histamine N-methyl-Transferase (HNMT) and monoamine oxidase B (MAOB). In total, we analysed data from 12 datasets, comprising samples from 225 individuals who died by suicide and 258 non-suicide controls including both healthy individuals and individuals with neuropsychiatric disorders who died by other causes. Samples consisted predominantly of adults aged between 18 and 75 years, with a mean age of approximately 45 years across studies. The gender distribution was predominantly male, accounting for approximately 65% of the total sample across groups. Using multivariate meta-analysis models, we found significantly elevated HRH2 receptor expression, particularly in brain regions critically associated with mood regulation, such as the hippocampus and orbitofrontal cortex, in individuals who died by suicide when compared to individuals who did not die by suicide. Additionally, we also found significant region-specific expression changes for HNMT and HDC, notably decreased HNMT expression in the amygdala and hippocampus, and divergent changes in HDC expression in the temporal pole (increased) and thalamus (decreased). These findings underscore the complexity of histaminergic dysregulation as a molecular substrate in suicide, highlighting its potential as a target for biomarker development and therapeutic interventions aimed at suicide prevention.