The causal relationship between depression and chronic pancreatitis: A Mendelian randomization study

Observational studies have suggested a high prevalence of depression among patients with chronic pancreatitis (CP). However, the effects of depression on CP and the causal relationship between the two conditions remain unclear. We performed two-sample and multivariable Mendelian randomization (MR) analyses, as well as a two-step MR analysis, to investigate their causal associations. Data on depression and CP were obtained from summary statistics of non-overlapping samples in a genome-wide association study. Two-sample and multivariable MR analyses were conducted to explore the association between depression and CP. A subsequent two-step MR analysis explored the causal pathways between the two conditions and the role of mediators in this process. Genetically, predicted depression (per 1 standard deviation) showed a positive association with CP (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.03 – 1.86; P = 0.03). The causal relationship was confirmed after adjusting for smoking, drinking, type 2 diabetes, body mass index, and triglycerides. We found that triglycerides (OR: 1.02; 95% CI: 1.01 – 1.04; P = 0.004), type 2 diabetes (OR: 1.03; 95% CI: 1.01 – 1.06; P = 0.030), and smoking initiation (OR: 1.06; 95% CI: 1.01 – 1.13; P = 0.046) may mediate the causal relationship between depression and CP, with the mediating effect accounting for 6.14%, 7.84%, and 17.06% of the total effect, respectively. Our study provides evidence for an independent causal effect of depression on CP, offering new insights into the correlation between depression and inflammation. Further research is necessary to clarify the pathophysiological mechanisms underlying this causal association.