Although complex bidirectional dysregulations of gut–brain axis is considered the key mechanism of developing FGIDs, the causal relationship between the two remains unclear. In this MR analysis, by using the largest GWAS results to date, we demonstrated a causal relationship from depression instead of anxiety to three common FGIDs, including FD, constipation, and IBS. A bidirectional causal relationship between anxiety, depression and IBS was also identified. However, there was no evidence of a causal relationship between constipation or FD to anxiety or depression.
FGIDs comprise a large group of functional gastrointestinal disorders, with constipation, FD, and IBS accounting for more than 50% of all FGIDs.36 For the first time, we identified depression as the etiology of the three most common FGIDs. This is consistent with previous observational studies suggesting that depression was associated with an increased risks of FD, constipation an IBS.9–11 Additionally, there were also several studies found that depression was associated with development of other FGIDs, including functional diarrhea and functional abdominal pain and functional heartburn.37–39 These results indicate that depression may be a common etiology of FGIDs. However, because of the lack of GWAS data related to other FGIDs, we are currently unable to determine the causal relationships, which deserves further exploration in the future.
A recent MR study by Eijsbouts et al. have also suggested a bidirectional causal relationship between depression and IBS. However, this study reported inconsistent result on the causal relationship from IBS to anxiety. One of the reasons may be the effects from multiethnicity, which may have decreased their statistical power with potential false negative results.18 Whereas, our study minimized such potential biases by restricting sample to European populations, which revealed a causal relationship between IBS to anxiety.
Conventional observational studies have confirmed that FD is longitudinally associated with increased risk of depression and anxiety.9, 10 Besides, depression and anxiety are more prevalent in individuals with chronic constipation than in the general population.12 However, the current study has provided suggestive evidence that genetically predicted constipation or FD is unlikely to be causally associated with the risks of depression. The main reason may be due to the fact that there were few genetic variants (p < 5x10− 8) of constipation or FD in the datasets to date, which may have decreased their statistical power with potential false negative results. However, the null finding was identified by utilizing more SNPs with a weaker (P < 1x10− 5) association with constipation or FD as the genetic instruments throughout the MR IVW and sensitivity analyses. Another reason is the burden of chronic illness can lead to depression. Living with chronic illness, regardless of the diagnosis, is known to cause significant psychological disorders.40 Since many chronic conditions can lead to constipation or dyspepsia, 41, 42 the association between constipation or dyspepsia and depression reported in observational studies may reflect a reverse causality or residual confounding. Regardless, further investigations should be carried out to verify these findings.
Our study further support the concept of bidirectional brain-gut pathways in FGIDs by using MR analysis. It highlights the importance of integrated management of depression, anxiety and common FGIDs together. Firstly, as depression is a causal risk factor for FGIDs, appropriate management of depression may lead to alleviated FGIDs symptoms or improved health-related quality of life. The beneficial effects of anti-dpression on IBS and constipation has been reported in previous studies.43–45 Thus, future clinical trials assessing the effectiveness of novel treatments related to deression on FGIDs may be valuabe. Secondly, earlier or more widely screening for depression in FGIDs patients can be performed. In particular, those with common risk factors (e.g. female gender, life stress or insomnia) for depression may be the target group that warrants such a strategy, and such early screening may lead to a reduced risk of worsening of common FGIDs.46, 47 Thirdly, clinicians may monitor gastrointestinal symptoms in depression patients because they bear a burden of increased risk of FGIDs due to the presence of depression.
There are several limitations in this study. Firstly, the diagnosis of three common FGIDs were not standardized. ROME IV criteria, 2 as the widely used diagnostic criteria of FGIDs, are not strictly followed in the three large cohorts included in our study, which will bias our results. For example, the overall prevalence of FD was only 2.45%, much lower than that reported in the epidemiological studies,48 which may lead to a dilution of the causal effect of FD to depression or anxiety. Secondly, the statistical power of some findings is insufficient, which is related to the limited sample size and instrumental variables. A larger sample size of GWAS data is needed in the future. Thirdly, there was partial samples overlap for the two summary statistics implemented in our study, which is indeed a known bias factor in the presence of weak instrumental variables when conducting two-sample MR.49 However, there are no weak instrumental variables in our univariate MR. In addition, our analysis decrease the possibility of false-positive findings by replicating the results in two non-overlapping sample (IBS from FinnGen). Finally, the current study relied on genetic data conducted in a population of European ancestry, which limits the generalizability of the present findings in other ancestry.
In conclusion, this study suggests that depression is a causal risk factor for common FGIDs. A bidirectional causal relationship between anxiety, depression and IBS was also identified. Clinicians may need to pay attention to depression in FGIDs patients and monitor gastrointestinal symptoms in those with depression or anxiety.