687. Unraveling the suicide-inflammation axis and the moderating role of early life stress insights from polygenic risk score analyses

Abstract

Abstract Background Elucidating the biological underpinnings of suicidal behavior and identifying reliable biomarkers remains a major challenge in suicide research. Equally critical is delineating the role of environmental factors, particularly early-life adversity but also acute and recent stressors in modulating suicide risk, likely through distinct neurobiological pathways. Emerging evidence suggests inflammation as a key candidate mechanism in the background of stress-associated suicidal behaviours. This association is further supported by elevated suicide risk observed in individuals with chronic inflammatory and autoimmune disorders, suggesting shared pathophysiological pathways beyond purely psychological responses. Furthermore, chronic low-grade inflammation has also been consistently linked to early-life stress and mediating the effects of early adversities on mental health lasting into adulthood, which highlights the need of understanding the relationship between early traumas, inflammation, and suicide risk in order to aid screening and prevention as well. Aims & Objectives The present study therefore aimed to investigate genetic overlap between a range of inflammatory and autoimmune conditions and suicidal behavior, employing a polygenic risk score approach. Method Summary statistics from published GWASes for common autoimmune and inflammatory disorders were used to calculate polygenic risks scores for these disorders using LDPRED2. Using these PRSs, actual suicidal ideation and previous suicide attempts were predicted using linear and logistic regression models. The moderating effects of early life stress and recent stressors were investigated using interaction models. Results Only PRS calculated for metabolic syndrome predicted previous suicide attempts (β=0.3269, p=0.0161) or current suicidal ideation (β=0.2577, p=0.0308) independently of early or recent life stress. However, in case of all other inflammatory conditions, significant results emerged only in interaction with early life stress. In case of current suicidal ideation, when considering the interaction effect of current stress, PRS for autoimmune thyroid disorder showed a significant effect (β=0.9728, p=0.0488), and when considering the interacting effect of early childhood traumas, highly significant effects for PRS-s calculated for SLE attempts (β=0.414, p=0.0003) and atrophic gastritis attempts (β=0.2289, p=0.0125) emerged. Discussion & Conclusions Our results suggests that somatic disorders associated with chronic immunological activation or inflammation are associated with suicidal phenotypes especially in those exposed to early life stress. Further studies are needed to establish if the effect characterises suicidal behaviour in general or there are specific inflammatory biotypes of suicide.