Association of mental disorders with sepsis: a bidirectional Mendelian randomization study

Abstract

Background: Substantial research evidence supports the correlation between mental disorders and sepsis. Nevertheless, the causal connection between a particular psychological disorder and sepsis remains unclear.

Methods: For investigating the causal relationships between mental disorders and sepsis, genetic variants correlated with mental disorders, including anorexia nervosa (AN), attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), panic disorder (PD), posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and tourette syndrome (TS), were all extracted from the Psychiatric Genomics Consortium (PGC). The causal estimates and direction between these mental disorders 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. Meta-analysis, multivariable MR, and mediation MR were conducted to ensure the credibility and depth of this research.

Results: The presence of AN was in relation to a greater likelihood of sepsis (OR 1.08, 95% CI 1.02-1.14; p = 0.013). A meta-analysis including validation cohorts supported this observation (OR 1.06, 95% CI 1.02-1.09). None of the investigated mental disorders appeared to be impacted when sepsis was set as the exposure factor. Even after adjusting for confounding factors, AN remained statistically significant (OR 1.08, 95% CI 1.02-1.15; p = 0.013). Mediation analysis indicated N-formylmethionine levels (with a mediated proportion of 7.47%), cystatin D levels (2.97%), ketogluconate Metabolism (17.41%) and N10-formyl-tetrahydrofolate biosynthesis (20.06%) might serve as mediators in the pathogenesis of AN-sepsis.

Conclusion: At the gene prediction level, two-sample bidirectional MR analysis revealed that mental disorder AN had a causal association with an increased likelihood of sepsis. In addition, N-formylmethionine levels, cystatin D levels, ketogluconate metabolism and N10-formyl-tetrahydrofolate biosynthesis may function as potential mediators in the pathophysiology of AN-sepsis. Our research may contribute to the investigation of novel therapeutic strategies for mental illness and sepsis.

Keywords: Mendelian randomization; anorexia nervosa; blood metabolites; gut microbiome; inflammatory factors; mental disorders; sepsis.

Figure 1

Flowchart overview of the Mendelian randomization study.

Figure 2

Forest plot of causal associations between 10 mental disorders and sepsis risk. BD, bipolar disorder; MDD, major depressive disorder; SCZ, schizophrenia; AN, anorexia nervosa; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; ADHD, attention-deficit hyperactivity disorder; PTSD, posttraumatic stress disorder; TS, tourette syndrome; PD, panic disorder; SNP, single nucleotide polymorphism; IVW, inverse variance weighted; OR, odds ratios; CI, confidence intervals; p-value < 0.05 was considered significant.

Figure 3

Scatter plot of Mendelian randomization analysis for the associations of anorexia nervosa with the risk of sepsis. SNP, single nucleotide polymorphism; MR, Mendelian randomization.

Figure 4

Leave-one-out plot for Mendelian randomization analysis of the causal effect of anorexia nervosa on the risk of sepsis. MR, Mendelian randomization.

Figure 5

Meta-analysis of the causal effect of AN on sepsis. SE, standard error; OR, odds ratio; CI, confidence interval; p < 0.05 was considered significant.

Figure 6

Genetically predicted association of AN with sepsis after adjusting for confounding factors. OR, odds ratio; CI, confidence interval; p-value < 0.05 was considered significant.

Figure 7

The mediating effect of AN on sepsis via blood N-formylmethionine levels and cystatin D levels accompanied by ketogluconate metabolism and N10-formyl-tetrahydrofolate biosynthesis in the gut microbiome. SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; p-value < 0.05 was considered to indicate statistical significance.