Evaluation of bi-directional causal association between depression and sepsis: a Mendelian randomization study

Abstract

Background: The relationship between depression and sepsis is interconnected, but the nature of their association remains unclear. Our aim is to determine whether the genetic susceptibility to depression is related to sepsis and 28-day mortality from sepsis.  Methods: In the Mendelian randomization (MR) study, we accessed exposure data from Genome-wide association study (GWAS) and the FinnGen consortium. We employed univariable and reverse MR analyses to explore potential associations between depression and sepsis and its 28-day mortality. The causal estimates and direction between depression and sepsis were evaluated employing a two sample bidirectional MR strategy. The inverse variance weighted (IVW) method was the primary approach utilized. Various sensitivity analyses were performed to confirm the validity of the causal effect. Causality was inferred between correlated traits by Mendelian Randomization analyses. Results: Bidirectional Mendelian randomization analyses demonstrated no evidence of causal associations: genetically predicted depression showed no significant effect on sepsis risk (IVW OR=1.102, 95%CI=0.951-1.277, p=0.197), while genetic liability to sepsis was not associated with depression risk (IVW OR=0.992, 95%CI=0.937-1.051, p=0.786). Sensitivity analyses using weighted median and MR-Egger methods revealed consistent null effects with <5% variation in effect estimates. Furthermore, genetically instrumented depression exhibited no causal impact on 28-day sepsis mortality (IVW OR=1.051, 95%CI=0.746-1.482, p=0.775), with all confidence intervals encompassing unity (OR=1). Conclusions: In summary, this bidirectional Mendelian randomization study provides robust evidence that genetic susceptibility to depression is not causally associated with the risk of sepsis or 28-day mortality from sepsis. Similarly, reverse MR analysis revealed no significant causal effect of sepsis on the risk of depression. These findings challenge the hypothesis of a direct genetic link between depression and sepsis, suggesting that the observed epidemiological associations may be driven by shared environmental factors, inflammatory pathways, or other confounding variables rather than a direct causal relationship. The lack of a genetic causal association highlights the importance of exploring alternative mechanisms, such as immune dysregulation, metabolic disturbances, or psychosocial factors, that may underlie the complex interplay between mental health and critical illness outcomes. Future research should focus on identifying potential mediators, including inflammatory biomarkers (e.g., IL-6, TNF-α) and metabolic pathways, to better understand the pathophysiology of sepsis and its long-term psychological sequelae. Despite the negative findings, this study contributes to the growing body of literature on the relationship between mental health and sepsis by employing a rigorous MR design that minimizes confounding and reverse causality. The results underscore the need for further investigation into the role of non-genetic factors in the development of sepsis and its outcomes, as well as the potential for targeted interventions to improve the mental and physical health of sepsis survivors.