Page 61 - JCBP-3-3

Journal of Clinical and
Basic Psychosomatics Depression and chronic pancreatitis: MR study

1. Introduction association study (GWAS) to explore the causal
relationship between depression and CP. Multivariable MR
Chronic pancreatitis (CP) refers to a fibro-inflammatory analysis was used to adjust for other exposures, revealing
syndrome of the pancreas, leading to irreversible damage the direct causal effect of depression on CP. In addition, a
to pancreatic tissue or function. It most commonly occurs two-step MR analysis was conducted to identify potential
due to heavy alcohol consumption, cigarette smoking, mediators and sensitivity analysis was performed to assess
environmental insults, genetic predispositions, and other the stability of the results. We also identified shared genetic
causes. The clinical manifestations of CP include varying loci based on the summary statistics of CP and depression
1-4
degrees of exocrine pancreatic insufficiency, pancreatic from the FinnGen database.
stones, common bile duct stenosis, diabetes mellitus,
3,5
and an increased risk of pancreatic cancer. CP affects 2. Materials and methods
approximately 42 – 73/100,000 people in the United States
and up to 50% of individuals globally, with a mortality rate 2.1. Research design
of about 0.09/100,000 persons worldwide. 3,4,6 Available MR is an epidemiological statistical method based on
surveys have shown that the physical and mental health causal inference, using IVs, such as single-nucleotide
decline, along with the reduced quality of life (QOL) polymorphisms (SNPs), that are highly correlated with
associated with CP, imposes an increasing medical and exposure factors. To ensure reliable MR analysis results,
16
economic burden on both families and society. Current three essential assumptions of MR analysis must be met.
7,8
16
studies suggest that long-term recurrent abdominal First, genetic variations used as IVs should be strongly
pain and other CP-related complications contribute to correlated with the exposure. Second, the selected IVs
these adverse outcomes, including the development of should not be associated with confounding factors. Third,
depression. 7,8 exposure should be the only pathway through which the
Depression is a common mood disorder characterized IVs influence the outcomes. 15
by a persistent low mood and a loss of interest or pleasure, To explore the causal link between CP and depression,
often accompanied by deficits in daily functioning. we conducted a two-sample bidirectional MR analysis.
9,10
Surveys show that nearly one in five people will experience a In the first analysis, depression was treated as the
depressive episode at some point in their lifetime. Patients exposure and CP as the outcome, and in the second
11
with depression are at a higher risk for recurrence, suicide, analysis, the roles were reversed. Multivariable MR
and other mental health complications. Inflammatory analysis was used to adjust for potential confounders
processes have been implicated in the pathophysiology of to better isolate the direct causal effect of depression
depression, and there is growing evidence that depression on CP. We then explored potential mediators based on
12
is associated with inflammatory biomarkers. Controlling depression outcomes and CP exposure factors identified
inflammation may provide therapeutic benefits for in relevant Mendelian research studies. 18,19 A two-step
depression. Research indicates that depression can MR approach was employed to evaluate the mediating
13
elevate the incidence and mortality rates of conditions role of potential mediators in the relationship between
such as diabetes and obesity, both of which are linked to depression and CP. For CP, depression, confounding
increased inflammation. A growing body of studies has variables, and potential mediators, SNPs were used as
14
shown that patients with CP also have a high incidence genetic tools. These SNPs were derived from extensive
of depression. However, it remains unknown whether European GWAS meta-analyses that had previously been
long-term depression increases the risk of developing CP published. To minimize potential bias due to sample
through inflammatory and immune system dysfunction. overlap, we used CP summary statistics from FinnGen’s
Mendelian randomization (MR) is an epidemiological Finnish population sample, excluding the UK Biobank
data analysis method that explores causal relationships. It dataset, as the UK Biobank is part of the depression
uses genetic variations closely related to exposure factors meta-analysis. The overall study design is depicted in
as instrumental variables (IVs) to evaluate the causal link Figure 1.
between exposures and outcomes. 15-17 The advantages of We employed a two-sample MR framework to explore
MR include minimizing residual confounding factors and the bidirectional causal relationship between depression
overcoming reverse causality, as genetic variations are and CP, aiming to provide new insights into the etiology
randomly assigned at conception and remain unaffected and prevention of CP. MR analysis was conducted using
by disease status. In this study, we employed a two-sample the R software packages TwoSampleMR version 0.5.7 and
bidirectional MR analysis using summary statistical MendelianRandomization (version 0.9.0). In addition,
data from non-overlapping samples in a genome-wide this study was conducted according to the Strengthening

Volume 3 Issue 3 (2025) 55 doi: 10.36922/jcbp.5892