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. 2024 Mar 4;12(3):e2413. doi: 10.1002/mgg3.2413

Major depressive disorder and the risk of irritable bowel syndrome: A Mendelian randomization study

Ruiming Zhu 1, Nan Zhang 1, He Zhu 1, Fudong Li 1, Hong Xu 1,✉
PMCID: PMC10912794  PMID: 38439604

Abstract

Background

The association between major depressive disorder (MDD) and irritable bowel syndrome (IBS) has been found in observational research; however, the causative relationship between MDD and IBS remains uncertain. Using the two‐sample Mendelian randomization (MR) approach, we attempted to examine the causal effect of MDD on IBS.

Methods

Independent genetic variants for MDD identified by Howard et al. based on a genome‐wide meta‐analysis were selected for this study. Gene‐Outcome associations for IBS were gathered from UK Biobank and FinnGen databases. The MR analysis included inverse variance weighted (IVW), MR‐Egger regression, weighted median, weighted mode, and MR‐PRESSO sensitivity analyses.

Results

FinnGen database subjected to inverse variance weighted (IVW) analysis revealed that MDD may be a risk factor for the development of IBS (OR = 1.356, 95% CI: 1.125–1.632, p = 0.0013). The same finding was reached in UK Biobank for IVW (OR = 1.011, 95% CI: 1.006–1.015, p = 3.18 × 10−7), MR‐Egger progression (OR = 1.030, 95% CI: 1.008–1.051, p = 0.007), and weighted median (OR = 1.011, 95% CI: 1.005–1.016, p = 0.0001).

Conclusion

Our findings supported a causal relationship between MDD and IBS, which may have implications for the clinical management of IBS in individuals with MDD.

Keywords: irritable bowel syndrome, major depressive disorder, Mendelian randomization

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1. INTRODUCTION

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by the absence of detectable pathological changes (Black & Ford, 2020; Ford et al., 2017). The characterization of IBS involves the presence of recurring abdominal pain, with an average occurrence of at least 1 day per week over the past 3 months. The syndrome is linked to a minimum of two criteria from the following: association with defecation, alteration in stool frequency, and changes in stool form (appearance). Additionally, these criteria must persist consistently for the last 3 months, and the onset of symptoms should precede the diagnosis by a minimum of 6 months (Lin & Chang, 2020). In severe cases, the patients often complain of incomplete evacuation and increased gas or mucus in the stool at least 1 day per week for nearly 3 months (Black & Ford, 2020). In recent years, IBS has been considered a common functional gastrointestinal disorder, involving dysregulation of the gut–brain interaction and affecting approximately 4.1% of the global population. Due to variations in research methods and differences in genetics, culture, lifestyle, and dietary traditions among different countries, it exhibits significant heterogeneity in epidemiology (Black et al., 2020). Treatment for IBS is extremely expensive, with direct annual costs ranging from $1562 to $7547 per patient and indirect costs ranging from $791 to $7737 (Nellesen et al., 2013). IBS has a significant impact on the quality of life of patients, particularly in females under the age of 50 (Black & Ford, 2020; Lovell & Ford, 2012). In fact, those patients with severe symptoms appear to be more inclined to accept a considerable degree of risk to alleviate their symptoms. Taking a questionnaire‐based study as an example, the research indicates that individuals with IBS primarily characterized by severe diarrhea symptoms are willing to assume an average risk of 10.2% ± 15.7% of sudden death to gain a hypothetical 99% chance of cure. Furthermore, the study reveals that individuals with IBS, in pursuit of pain relief, are willing to incur an average monthly cost of $73 (if annual income is <$75,000) and an average monthly cost of $197 (if annual income is > $75,000) (Shah et al., 2021). Another survey also discloses that IBS patients are willing to sacrifice 25% of their remaining life expectancy, averaging 15 years, to be free from symptoms. (Drossman et al., 2009). Acquiring a more profound comprehension of the risk factors associated with IBS, with a specific focus on psychological health factors, aids in clarifying the pathogenesis of the syndrome. Implementing targeted preventive strategies for individuals with a high risk of developing IBS can significantly diminish the probability of IBS onset in patients, thereby mitigating the related economic burdens and medical pressures.

Major depressive disorder (MDD) is one of the most prevalent mental disorders and a leading cause of disability, affecting over 300 million individuals of all ages worldwide. (Nomura et al., 2017) Though MDD has a varied etiology, the association of IBS has been a major focus of research in recent years. A meta‐analysis indicates that the risk of irritable bowel syndrome (IBS) is approximately twice as high in depressed individuals as in healthy individuals (RR 2.06, 95% CI 1.44–2.92) (Sibelli et al., 2016). Approximately more than 25% of individuals with IBS experience the challenges of depressive symptoms (Zamani et al., 2019). People with IBS tend to have higher levels of depression than healthy individuals and those with inflammatory bowel disease, indicating a strong correlation between depression and IBS (Fond et al., 2014; Lee et al., 2017; Roohafza et al., 2016; Zamani et al., 2019). Due to the observational nature of the study—its susceptibility to confounding variables and reverse causality, the depth of the causal relationship between MDD and IBS is currently ambiguous.

Mendelian randomization (MR) is a novel epidemiological statistical method predicated on the idea that genetic variants are assigned randomly during conception and are therefore unaffected by the environment (Morris et al., 2022). This method uses instrument variables strongly associated with exposure factors to minimize bias and avoid reverse causation by simulating randomized controlled studies (RCT) (Burgess et al., 2019). Consequently, MR results are more reliable than those of conventional studies. In this study, we used a two‐sample of MR to investigate the causal relationship between MDD and IBS to improve IBS in patients and the prevention and treatment of symptomatic cases.

2. METHODS

2.1. Study design

To clarify the causal relationship between MDD and IBS, we conducted two sets MR analyses that complemented each other. To ensure that the results of this analysis are objective and reliable, we have chosen instrument variables that satisfy the following three assumptions (Burgess et al., 2017): first, genetic variation as an instrument variable is closely related to exposure factors (correlation assumption); second, instrument variables are independent of any confounding factors (independence assumption); and third, instrument variables are not directly related to outcomes: they can only influence outcomes through exposure factors (exclusivity assumption) (Burgess et al., 2019). Since all data in this document are derived from publicly available GWAS summary statistics, no additional ethical approval was required. An overview of the design of this study is shown in Figure 1.

FIGURE 1.

FIGURE 1

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Experimental design of MR analysis. (a) Mendelian randomization: Three major assumptions for the selection of instrumental variables. (b) MR analysis from depression to IBS: The list of genetic variants associated with depression was derived from a genome‐wide meta‐analysis of depression performed by Howard et al. The IBS gene correlation was derived from the most recent UK Biobank and FinnGen data sets.

2.2. Data source

Genetic variants associated with depression were derived from a genome‐wide association meta‐analysis of depression conducted by Howard et al., which included 33 cohorts of the Psychiatric Genomics Consortium (PGS) (excluding UK Biobank and 23andMe data) (43,204 cases and 95,680 controls), UK Biobank (127,552 cases and 233,763 controls), and the 23andMe discovery cohort (75,607 cases and 231,747 controls) (Howard et al., 2019). The total number of individuals in this data is 807,553 (246,363 cases and 561,190 controls). In this study, depression was diagnosed based on a broader self‐statement defining depression and clinically diagnosed MDD in a hospital setting.

Gene‐outcome associations for the IBS were obtained from the most recent UK Biobank and FinnGen databases. The specific diagnostic criteria for IBS are described in the previous introduction. In the FinnGen study, IBS was defined as IBS with diarrhea according to the international code of disease version 10 (ICD10). The data set consists of 8116 cases and 276,683 controls (finngen_R8_K11_IBS, https://www.finngen.fi/en). The data we selected from the UK Biobank database contains 10,939 cases and 451,994 controls (Elsworth et al., 2020). A total of 9,851,867 SNPs were available for analysis (ukb‐b‐2592, http://www.nealelab.is/uk‐biobank). The diagnosis of IBS used in this study was self‐reported and obtained from verbal interviews conducted by trained nurses.

A common source of bias for MR analysis is population stratification, as the frequency of the same allele can vary among populations from different lineages (Larsson et al., 2019). To avoid this effect, we made sure to include all individuals’ data belonging to European ancestry.

2.3. IV selection

Using the aforementioned database, we initially selected single‐nucleotide polymorphisms (SNPs) associated with MDD by meeting the threshold for genome‐wide significance (p < 5 × 10−8) and removed SNPs with linkage disequilibrium (LD) by r 2 < 0.001, window size = 10,000 KB. To meet the exclusivity assumption of instrumental variables selection (Burgess et al., 2017), the correlation data of SNPs associated with exposure factors were extracted from data sets of outcome summaries (FinnGen and UK Biobank studies), and then removed SNPs that were directly associated with the outcome (p < 5 × 10−5). In this study, palindromic and incompatible SNPs were removed based on the effect of allele frequency.

Irritable bowel syndrome can also be affected by abdominal obesity, gastrointestinal infections, somatic symptoms (pains, e.g., joint pain and migraine), and quality of life (Black & Ford, 2020; Enck et al., 2016). To prevent exposure factors from affecting the results through these confounders, we used PhenoScanner to test each SNP for possible associations with confounders (Staley et al., 2016), and SNPs that could violate the assumption of independence were removed.

F‐statistics were calculated as R2 (N − 2)/1 − R2, a method to assess the statistical validity of instrument variables, which we used to eliminate weak instrument variables (F < 10) (Burgess & Thompson, 2011). After stringent filtering, we obtained all SNPs that could satisfy all three instrumental variable selection assumptions (Burgess et al., 2017).

2.4. Statistical analyses

We will explore the causal relationship between MDD and IBS using four methods, inverse variance weighted (IVW), MR‐Egger regression, weighted median, and weighted mode. IVW is by far the leading MR analysis, which involves a reverse variance weighted meta‐analysis of the Wald ratio of individual SNPs. Assuming that instrument variables only influence outcomes through our selected exposure factors, it could be the most statistically efficient method if our selected instrument variables satisfy the three MR assumptions in the previous section (Burgess et al., 2013). The Egger regression relaxes instrumental variables assumptions, and unbiased estimates of causal effects can be obtained even if all of the instrumental variables are not valid. This could be achieved only if the Instrumental Strength Independent of Direct Effect (InSIDE) condition that the horizontal pleiotropic effects are independent of the SNPs satisfies an instrumental variable (Bowden et al., 2015). In comparison to Egger regression, the weighted median method does not consider horizontal pleiotropic, assuming that at least half of the instrumental variables are valid to draw cause‐and‐effect conclusions (Bowden et al., 2016). Weighted mode method is to group the SNP clusters based on the similarity of the causal effects estimated by different SNP, and then estimate the causal effects based on the largest number of SNP clusters (Hartwig et al., 2017). While MR‐Egger regression, weighted median, and weighted mode are not as effective as IVW, they provide reliable cause‐and‐effect estimates in a broader context, making MR results more reliable.

Sensitivity analysis made MR results more reliable by assessing and modifying for pleiotropy and heterogeneity among SNPs. We tested all heterogeneity among SNPs using Cochran's Q test, where heterogeneity can be considered when the p < 0.05. The Intercept of MR‐Egger and MR‐Pleiotropy Residential Sum and Outlier Methods (MR‐PRESSO) were used to evaluate pleiotropy, with the former deviating from zero having apparent pleiotropy (Burgess & Thompson, 2017), while the latter assessed and corrected pleiotropy by detecting and kicking out significant outliers (Ong & MacGregor, 2019). Leave‐one‐out analysis ensures that the results are reliable by taking out the SNP item by item to assess whether the results are more influenced by a single SNP.

All statistical analyses involved in this MR analysis were performed by “TwoSampleMR” and “MRPRESSO” in R software (version 4.2.1).

3. RESULTS

3.1. Development of MDD instrument variables

We obtained 137 SNPs after filtering at the genome‐wide significance level (p < 5 × 10−8) and removing linkage disequilibrium (r 2 < 0.001, window size = 10,000 KB). Using the FinnGen study, we merged the results database and removed four palindromes and incompatible SNPs (rs1933802, rs2029865, rs2247523, rs2876520), and obtained 68 SNPs. Similarly, we obtained 66 SNPs from the UK Biobank database after the removal of five incompatible palindromes and SNPs (rs12052908, rs1933802, rs2029865, rs2247523, and rs2876520). No SNPs directly linked to outcome were identified in FinnGen and UK Biobank. Finally, we used PhenoScanner to remove the confounders and were left with 57 and 56 SNPs in FinnGen and UK Biobank, respectively, that met the three assumptions of MR. The F‐statistic for all SNPs was greater than 10 and no weak instrumental variables were found. The details of these SNPs are listed in Tables S1 and S2.

3.2. IBS in FinnGen study

We employed IVW as the major method of MR analysis to investigate the causal link between MDD and IBS. Thus, MDD was found to be an independent risk factor for IBS (OR = 1.356, 95% CI: 1.125–1.632, p = 0.0013). Although the MR‐Egger regression (p = 0.201), weighted median (p = 0.09), and weighted mode (p = 0.783) approaches did not produce statistically significant findings, they were all compatible with the IVW method in a positive direction (Figure 2). Next, we applied Cochran's Q test to the 57 SNPs included in this study and found no evidence of heterogeneity (Q = 52.22, p = 0.61). The MR‐Egger regression, whose intercept was −0.0093 (p = 0.48), did not detect pleiotropy. The MR‐PRESSO method could not detect any outliers of significance. Scatter plots (Figure 3) display the individual SNP effect as well as the cumulative effect from each approach for each outcome data set. The leave‐one‐out sensitivity analysis likewise revealed that no SNP had a substantial effect on the overall picture (Figure S1). In addition, the funnel plot was symmetrical, demonstrating the absence of pleiotropy (Figure S3).

FIGURE 2.

FIGURE 2

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MR results.

FIGURE 3.

FIGURE 3

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Scatter plot of MR analyses from MDD to IBS from FinnGen.

3.3. IBS in the UK biobank study

After removing a major outlier using the MR‐PRESSO approach (rs6783233), we concluded that MDD may be a risk factor for IBS utilizing IVW as the primary method for MR analysis (OR = 1.011, 95% CI: 1.006–1.015, p = 3.18 × 10−7). As complementary methods, MR‐Egger regression (OR = 1.030, 95% CI: 1.008–1.051, p = 0.007) and weighted median (OR = 1.011, 95% CI: 1.005–1.016, p = 0.0001) also lead to the conclusion that MDD and IBS may be closely related. Although the weighted mode (p = 0.06) approaches did not produce statistically significant findings, it was all compatible with the IVW, MR‐Egger progression, and weighted median method in a positive direction (Figure 2). Next, we applied Cochran's Q test to the 56 SNPs included in this study and found no evidence of heterogeneity (Q = 70.69, p = 0.06). The MR‐Egger regression, whose intercept was −0.0005 (p = 0.07), did not detect pleiotropy. The scatter plot is displayed in Figure 4. The leave‐one‐out sensitivity analysis likewise revealed that no SNP had a substantial effect on the overall picture (Figure S2). Likewise, roughly symmetrical funnel plots imply the absence of pleiotropy (Figure S4).

FIGURE 4.

FIGURE 4

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Scatter plot of MR analyses from MDD to IBS from UK Biobank.

4. DISCUSSION

A prior meta‐analysis revealed that, in contrast to individuals with inflammatory bowel disease, those diagnosed with IBS commonly display heightened manifestations of depression and anxiety (Geng et al., 2018). Another systematic review and meta‐analysis related more than a quarter of patients with IBS to depressive symptoms (Zamani et al., 2019). Furthermore, Sibelli et al. discovered that the risk of IBS in depressed individuals was approximately twofold that of normal individuals (Sibelli et al., 2016). However, it is not known whether psychological symptoms such as depression are due to IBS' effects on individuals or the cause of gastrointestinal symptoms (Van Oudenhove et al., 2016). A recent epidemiological study revealed that in two‐thirds of patients with IBS and psychological symptoms such as depression, gastrointestinal symptoms preceded mood swings, while in one‐third of patients, mood disorders preceded gastrointestinal symptoms (Koloski et al., 2016). However, the causal association between MDD and IBS remains unclear due to the fact that traditional observational studies are prone to reverse causality and susceptible to confounding variables.

This article innovatively employs MR to investigate the causal relationship between MDD and IBS from a genetic perspective. We employed genetic variation proxies for the exposure factor in individuals with MDD who have been exposed to this variant since conception. This could eventually limit the reverse causation (Qian et al., 2020) and reduced pleiotropy by removing genetic variations associated with confounding factors (Robinson et al., 2016). In this study, all GWASs data were gathered from European populations to decrease bias owing to population stratification. Using two separate two‐sample MR analyses, we investigated the causal link between MDD and IBS and discovered that MDD may contribute to the development of IBS. Consequently, this cause–effect relationship provided a foundation for the future prevention of IBS and has forecasted some applications in its treatment. Sensitivity analysis showed that the relationship between MDD and IBS via gene proxies was stable in both sets of MR analyses. Moreover, there was no evidence of directional pleiotropy in both sets of MR‐Egger analyses, indicating that the results of both sets of MR analyses are reasonable. Studies involving microbiomes and their influence on neurological and behavioral characteristics in animals have revealed that mice can transfer messages regulating emotions via microbes (Bercik et al., 2011). IBS patients had elevated levels of lipopolysaccharide‐induced tumor necrosis factor‐alpha compared to normal subjects, and the production of this factor was significantly associated with anxiety and depression (r = 0.59) (Liebregts et al., 2007). Unfortunately, limited by the database itself, when we attempted to analyze the causal relationship between IBS and MDD using the MR method, we were unable to select enough SNPs that met the criteria for compliance (p < 5e−8), even with a relaxed screening threshold.

A proposed biopsychosocial medicine model, the brain–gut axis, investigating a bidirectional neurohumoral communication system between the brain and the gut, has envisaged a focal point for exploring the association between gut disorders and psychological disorders (Van Oudenhove et al., 2016). Dysregulation of the brain–gut axis has been hypothesized to be the pathophysiological mechanism underlying the causal relationship between psychological disorders such as MDD and IBS (Mayer & Tillisch, 2011). Animal experimental studies to elaborate on the underlying mechanism indicate that emotional circuits in the brain are highly influenced by the colonic permeability and mucosal and systemic inflammation by synchronizing the efferent autonomic nervous system (ANS) and stress hormone system (hypothalamic‐pituitary‐adrenal axis [HPA]) (O'Malley et al., 2011). In humans, excessive activation of the HPA axis can increase interleukin six levels (Dinan et al., 2006). Anxiety and depression elevate the levels of pro‐inflammatory factors, tumor necrosis factor‐α, and the number of mast cells in the mucosa (Kindt et al., 2009; Liebregts et al., 2007; Piche et al., 2008). Similarly, changes in the gut environment can feed back to the brain, and microbes in the gut can influence the psychological status and chronic visceral pain of an individual via neurological, endocrine, and immune pathways (Cryan & Dinan, 2012). Several studies have demonstrated that probiotic supplementation can alter the central processing of emotional stimuli (Tillisch et al., 2013). Lukas Van Oudenhove et al. suggested that the microbiome–gut–brain axis holds promise as a novel treatment for functional gastrointestinal disorders such as IBS (Koloski et al., 2012; Van Oudenhove et al., 2016). Interestingly, four of the six genetic loci associated with IBS were also associated with anxiety and depression (NCAM1, CADM2, PHF2/FAM120A, and DOCK9), according to a large GWAS study suggesting that MDD and IBS may share a common genetic background (Eijsbouts et al., 2021).

Randomized controlled trials are the gold standard for obtaining medical evidence (Hariton & Locascio, 2018), but it is difficult to conduct an RCT on MDD and IBS due to time, cost, ethics, and other constraints. The MR analysis used in our study not only avoids reverse causality and confounding effects but also simulates a randomized controlled trial, making the analysis's results more trustworthy. However, our study does have some limitations. To begin with, the GWAS data we used were from European populations, and we were not certain that these findings are applicable to populations of other races, especially given the significant epidemiological differences in IBS. Second, due to the limitations of the IBS database, we were unable to obtain enough instrumental variables associated with IBS; thus, the reverse causality between MDD and IBS requires further investigation. Thirdly, the GWAS data used in this study are not individual raw clinical data but are procured from analytical studies that are publicly available. Hence at this moment, we could not investigate the effect of age, gender, etc. on this causal relationship in greater depth. Lastly, the potential overlap of samples may have some effect on our findings.

5. CONCLUSION

Our study discovered a causal relationship between MDD and IBS in a European population. MDD may be a risk factor for the development of IBS, and this finding suggests that patients with MDD should focus on preventing IBS.

AUTHOR CONTRIBUTIONS

Ruiming Zhu conceived and designed paper. Nan Zhang collected and analyzed data. He Zhu prepared figures. Fudong Li drafted a paper. Hong Xu edited and revised the manuscript. All authors read and approved the final version of the manuscript.

FUNDING INFORMATION

This work was supported by the Jilin Province Development and Reform Commission (Project Number: 2017C058‐2).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Since all data in this document are derived from publicly available GWAS summary statistics, no additional ethical approval was required.

CONSENT

Not applicable.

Supporting information

Data S1.

MGG3-12-e2413-s001.docx (392.3KB, docx)

ACKNOWLEDGMENTS

Not applicable.

Zhu, R. , Zhang, N. , Zhu, H. , Li, F. , & Xu, H. (2024). Major depressive disorder and the risk of irritable bowel syndrome: A Mendelian randomization study. Molecular Genetics & Genomic Medicine, 12, e2413. 10.1002/mgg3.2413

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1.

MGG3-12-e2413-s001.docx (392.3KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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