Abstract
Background
Some observational studies have suggested an association between insomnia and the risk of certain gastrointestinal disorders, such as gastroesophageal reflux, irritable bowel syndrome and peptic ulcers. However, the direction and magnitude of the causal relationship are difficult to determine due to confounding and reverse causation. The aim of this study is to explore the causal association between insomnia and a variety of gastrointestinal disorders from genetic level using Mendelian randomization.
Methods
We used a two-sample, two-way MR to analyze the link between insomnia and several gastrointestinal disorders (nine in total). Genetic variants used as instrumental variables were obtained from genome-wide association study (GWAS) data in the Open GWAS database. Causal effects were primarily estimated using inverse variance weighted (IVW), weighted median (WM) and MR-Egger. Horizontal pleiotropy was tested using MR-PRESSO and MR-Egger regression. Heterogeneity and sensitivity were assessed using Cochran's Q and leave-one-out.
Results
The forward MR analysis demonstrated significant causal effects of insomnia on gastroesophageal reflux disease (GERD) (IVW: OR = 1.864, 95%CI: 1.16–2.98, P = 0.009) and irritable bowel syndrome(IBS) (IVW: OR = 2.401, 95%CI:1.06–5.44, P = 0.036; WM: OR = 3.381, 95%CI:1.12–10.22, P = 0.031). Conversely, reverse MR analyses indicated protective associations against insomnia development for chronic gastritis (IVW: OR = 0.98, 95%CI: 0.97–0.99, P = 0.027), while revealing risk-enhancing effects for acute gastritis (IVW: OR = 1.013, 95% CI: 1.006–1.019, P < 0.001). No causal associations were observed between insomnia and the remaining five gastrointestinal conditions.
Conclusions
Through bidirectional MR analysis of nine gastrointestinal disorders, we provide genetic evidence for causal effects of insomnia on four conditions: gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), chronic gastritis, and acute gastritis.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-025-04228-9.
Keywords: Insomnia, Gastrointestinal disorders, Single nucleotide polymorphisms, Mendelian randomization, Genome-wide association studies
Introduction
The prevalence of gastrointestinal disorders is high, affecting about 40% of the general population [1]. Most people have gastrointestinal symptoms that cannot be clearly explained and are defined as functional gastrointestinal disorders, such as irritable bowel syndrome. Chronic gastrointestinal symptoms have substantial impact on quality of life, and the mechanisms are complex, involving gut microbiota, oxidative stress, gut-brain interactions, etc [2]. It is therefore important to investigate risk factors and take preventive measures in good time.
Sleep is an essential physiological activity for the human body, and a good night's sleep is vital for human health [3]. Insomnia is a common type of sleep disorder characterized by dissatisfaction with the quality and duration of sleep, difficulty falling asleep, awakening in the middle of the night or too early in the morning, or subjective complaints of poor sleep quality [4]. Compelling studies show that a quarter of adults are dissatisfied with their sleep and around 10% suffer from insomnia [5]. Chronic insomnia can lead to a variety of adverse outcomes, including cardiovascular disease [6], type 2 diabetes [6], respiratory disorders [7], soft tissue disorders [8], mental disorders [9]. These may be the result of insomnia-induced abnormalities in the autonomic nervous system and hypothalamic pituitary axis, inflammation, oxidative stress, etc. Additionally, several observational studies have indicated that insomnia is a risk factor for multiple gastrointestinal disorders, such as IBS [10], inflammatory bowel disease [11], peptic ulcers [12].
Amounts of large-sample genome-wide association studies (GWAS) now publicly available has enabled MR studies to overcome the limitations of small sample populations and a few genetic variants as instrumental variables, allowing researchers to use Mendelian randomization to assess causal associations between modifiable exposures and outcomes [13]. Compared with traditional observational studies, Mendelian randomization avoids the influence of confounding factors and reverse causality on the inference of causal associations at the genetic level, and has the advantages of being less expensive, shorter, and easier to conduct than randomized controlled trials (RCTs) [14–16].
Although there is substantial and convincing evidence of an association between insomnia and increased risk of gastrointestinal diseases, the existence of a direct causal relationship between the two variables has been controversial due to the influence of confounding and reverse causality effects. Previous literature ranges from studies focusing solely on IBS-insomnia relationships to two-sample MR analyses quantifying obesity-mediated pathways between insomnia and four GI disorders, with mediation proportions explicitly presenting [17, 18].
Therefore, in this study, we used two-sample, two-way MR to estimate the strength of the association between insomnia and various gastrointestinal diseases by combining the genetic variance of insomnia with the summary statistics of the genetic variance of various gastrointestinal diseases from different samples, to maximize the effects of confounding and reverse causation, and to explore potential causal relationships. The comprehensive results may provide clues and new insights for the prevention of gastrointestinal diseases to explore the genetic components predisposing to insomnia.
Materials and methods
Study overview
The two-sample, two-way MR was used to analyze causal associations between insomnia and a variety of gastrointestinal disorders, including nine major ones: gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), chronic gastritis, acute gastritis, gastric ulcer, ulcerative colitis, Crohn's disease, gastric cancer and colorectal cancer. The MR analyses were based on the following hypotheses: (i) genetic variants served as instrumental variables would be associated with exposure, (ii) genetic variants would be independent of confounders, (iii) genetic variants would affect outcomes only via exposure. The MR analysis followed the STROBE-MR statement strictly [19].
The study was conducted on the basis of publicly available databases as well as existing publications, therefore additional ethical approval was not required. Details of the study design are shown in Fig. 1.
Fig. 1.
The principles and main design of this Mendelian randomization study. IV: instrumental variable; SNP: single nucleotide polymorphism. Three pathways represent the three assumptions that need to be met for a Mendelian randomization study. They are in order from top to bottom: (i) genetic variants would be independent of confounders; (ii) genetic variants served as instrumental variables would be associated with exposure; (iii) genetic variants would affect outcomes only via exposure
Data sources
The data for insomnia is a European population sample of 336,082 participants published by the Neale Lab in 2017. The Open GWAS database, statistically summarizes GWAS data for many phenotypes, is a publicly available database from which we obtained GWAS data for insomnia and several gastrointestinal disorders. Crohn's disease data was published by the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) in 2015, with a European population sample of 20,883 participants22 [20]. GERD and IBS data were published in 2021, also from European populations, with 202,836 and 187,028 participants, respectively. Data on other gastrointestinal diseases except gastric cancer [21] were distributed by FinnGen. Details of the information was shown in Table 1.
Table 1.
Details of studies and datasets used in the study
| Phenotype | Sample Size | Web Source | First Author (year) | Consortium | Population |
|---|---|---|---|---|---|
| Insomnia | 336,965 | https://gwas.mrcieu.ac.uk/datasets/ukb-a-13/ | Neale (2017) | Neale Lab | European |
| Gastroesophageal reflux disease | 202,836 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_REFLUX/ | 2021 | FinnGen | European |
| Irritable Bowel Syndrome | 187,028 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_IBS/ | 2021 | FinnGen | European |
| Chronic gastritis | 194,908 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_CHRONGASTR/ | 2021 | FinnGen | European |
| Acute gastritis | 190,979 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_ACUTGASTR/ | 2021 | FinnGen | European |
| Gastric ulcer | 192,599 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_GULC/ | 2021 | FinnGen | European |
| Ulcerative colitis | 214,620 | https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_ULCER/ | 2021 | FinnGen | European |
| Crohn's disease | 20,883 | https://gwas.mrcieu.ac.uk/datasets/ieu-a-30/ | Liu et al. (2015) | IIBDGC | European |
| Gastric cancer | 476,116 | https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90018849/ | Sakaue S et al. (2021) | - | European |
| Colorectal Cancer | 218,792 | https://gwas.mrcieu.ac.uk/datasets/finn-b-C3_COLORECTAL/ | 2021 | FinnGen | European |
Selection of genetic variants
Regarding the exposure we are trying to explore, the selection of genetic variants for insomnia should fulfil the following conditions: SNPs have significance in genome-wide studies, and we screened SNPs with P < 5 × 10−8 to achieve this; Genetic variants as instrumental variables should be independent, we excluded the chain imbalance and ensured the independence of SNPs by setting r2 < 0.001 [22]. Additionally, the F statistic was calculated to avoid bias due to weak instrumental variables, and SNPs with F ≥ 10 were selected (F < 10 was considered a weak instrumental variable). The F statistic was calculated as F = beta2/se2 [23].
Statistical analysis
MR analyses were performed using the"TwoSampleMR"package. Inverse variance weighted (IVW), weighted median (WM) and MR Egger were used to estimate potential causality. As the most commonly used method in MR analysis providing greater accuracy in the absence of horizontal pleiotropy, the IVW method examines causality through meta-analysis of weighted effect estimates for each SNP and the MR-Egger method allows for horizontal pleiotropy with a larger bias compared to the IVW method. Moreover, the WM method is more robust than the previous two in the presence of an invalid IV, and provided that at least 50% of the IVs are valid [24–26].
We primarily evaluated the causality with the IVW method, expressed as odds ratio (OR) and 95% confidence interval (CI). P < 0.05 was considered statistically different. All statistical data were analyzed in R software (version 4.1.2). Additionally, we systematically scanned each SNP by PhenoScanner(http://www.phenoscanner.medschl.cam.ac.uk) to control for the effect of known confounders on estimation and excluded relevant SNPs before analysis.
Pleiotropy and sensitivity test
Pleiotropy is the association of genetic variants as IVs with the exposure and other potential risk factors influencing the outcome. As the presence of pleiotropy could obviously affect the results, we checked horizontal pleiotropy using MR-Egger regression and MR-PRESSO and removed outliers [27, 28], thus avoiding bias and confounding effects of pleiotropy-induced MR analysis. Additionally, we used Cochran's Q test to examine heterogeneity [29]. Finally, the"leave-one-out"sensitivity method was used to analyze the magnitude of the effect per SNP on the results to further check the stability of the results [30].
Results
The details of the data included in the study are shown in Table 1. The samples are all drawn from European populations to overcome selection bias with regard to ethnic homogeneity.
Characteristics of instrumental variables
We screened instrumental variables according to the criteria (P < 5 × 10 − 8, r < 0.001, kb = 10,000). Of these, 30 SNPs were selected as IVs for insomnia. The details of information is shown in Supplementary Table 1. The presented results include genes, chromosomal location, effect allele, other allele, effect allele frequency (EAF), beta value, standard error (SE), P value and F-statistics. The range of the F-statistic is 30–151, indicating the absence of weak instrumental variables. Summary statistics of instrumental variables associated with all outcomes are shown in Supplementary Table 2.
Insomnia and Gastroesophageal reflux disease
In the forward MR analysis, 28 SNPs were included in the MR analysis, then two SNPs with palindromic structures were removed (rs10280045, rs2644128). The IVW results show a causal association between insomnia and GERD (OR = 1.86, 95%CI:1.16–2.98, P = 0.009). It suggests that insomnia increases the risk of GERD, but WM and MR-Egger do not support the existence of causal association (WM: P = 1.98, MR-Egger: P = 0.776) (See Figs. 2 and 3). Conversely, the reverse MR analysis detected no evidence supporting genetic-level causal associations between GERD and insomnia(See Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Fig. 2.
Association between insomnia and nine gastrointestinal disorders; nSNP: the number of SNPs used as instrumental variables; CI: confidence interval;
Fig. 3.
Scatter plots of the Mendelian randomization analyses for the association of insomnia with the risk of nine gastrointestinal disorders. A Gastroesophageal reflux disease; B Irritable Bowel Syndrome; C Chronic gastritis; D Acute gastritis; E Gastric ulcer; F Ulcerative colitis; G Crohn's disease; H Gastric cancer; I Colorectal Cancer. The slope of each line corresponding to the estimated MR effect per method
Insomnia and irritable bowel syndrome
For the forward MR analysis, two SNPs with palindromic structures were removed, and the remaining 28 were included in the analysis. The IVW results show a causal association between insomnia and IBS (OR = 2.40,95%CI:1.06–5.44, P = 0.036), suggesting that insomnia increases the risk of IBS. WM results are consistent with IVW (OR = 3.381,95%CI:1.12–10.22, P = 0.031), but different from MR Egger (P = 0.346) (See Figs. 2 and 3). On the contrary, the reverse MR analysis found no evidence for a causal effect of IBS on insomnia using IVW, WM, or MR-Egger (See Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Insomnia and acute gastritis
The forward MR analysis revealed no significant causal association between insomnia and acute gastritis using IVW, WM, or MR-Egger(See Figs. 2 and 3). In the reverse analysis, both IVW (OR = 1.013, 95%CI: 1.006–1.019, P = 0.0001) and WM (OR = 1.014, 95%CI: 1.005–1.024, P = 0.0015) suggested a causal effect, whereas MR-Egger did not exhibit the similar result (P = 0.255) (See Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Insomnia and chronic gastritis
No evidence was detected for the causal link from insomnia to chronic gastritis in the forward analysis using all methods (IVW, WM, MR-Egger) (See Figs. 2 and 3). The reverse analysis showed a suggestive association via IVW (OR = 0.98, 95%CI: 0.97–0.99, P = 0.027), but this was not supported by WM (P = 0.162) or MR-Egger (P = 0.114)(See Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Insomnia and Crohn's disease
For the forward MR analysis, MR-PRESSO detected pleiotropy and found outliers when analyzing the causal relationship between insomnia and Crohn's disease. Eventually, a total of 25 SNPs were included after excluding SNPs with palindromic structures (rs10280045, rs2644128) and outliers (rs2132083, rs2863957, rs224071). None of the three methods (IVW, WM, MR-Egger) supported a causal association between insomnia and Crohn's disease, either before or after adjustment (See Figs. 2, and 3 and Supplementary Table 3). Conversely, the reverse MR analysis yielded no evidence supporting a causal relationship(See Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Insomnia and four other diseases
For gastric ulcer, ulcerative colitis, gastric cancer, and colorectal cancer, forward and reverse MR analyses found no evidence supporting a causal association with insomnia using IVW, WM, or MR-Egger (See Fig. 2, Fig. 3, Supplementary Fig. 1, Supplementary Fig. 2, and Supplementary Fig. 3).
Pleiotropy and sensitivity
There was no pleiotropy or heterogeneity in any of the results, except in the analysis of the causal relationship between insomnia and Crohn's disease. We used Cochran's Q test to examine heterogeneity, but the effect of heterogeneity on the results was not significant since we mainly used the random effects model of the IVW method. Details of the analysis are given in Supplementary Table 3 and Supplementary Fig. 1. Moreover, none of the SNPs were decisive for the causal inference according to the leave-one-out analysis, including the adjusted results for Crohn's disease (See Fig. 4 and Supplementary Fig. 4).
Fig. 4.
Leave-one-out sensitivity for insomnia on nine gastrointestinal disorders. A Gastroesophageal reflux disease; B Irritable Bowel Syndrome; C Chronic gastritis; D Acute gastritis; E Gastric ulcer; F Ulcerative colitis; G Crohn's disease; H Gastric cancer; I Colorectal Cancer
Discussion
In this study, we used a two-sample, two-way MR approach with genetic variants to explore a causal association between insomnia and a broad variety of gastrointestinal disorders. Through the IVW method as the primary outcome, we detected a direct causal association of insomnia on GERD and IBS (insomnia increases the risk of both). Conversely, the reverse MR revealed distinct causal pathways: chronic gastritis exhibited a negative causal relationship with insomnia, while acute gastritis displayed positive causality with insomnia risk. However, there is no evidence of a causal association between insomnia and other five gastrointestinal disorders.
Gastrointestinal diseases not only exhibit with gastrointestinal symptoms, but are usually accompanied by some symptoms outside the gastrointestinal tract [31], such as pain and fatigue, which greatly reduces the patient's quality of life and increases the disease burden. Therefore, the prevention and early treatment of gastrointestinal diseases is particularly important. Previous studies have shown that insomnia may increase the risk of gastrointestinal disease. Xu Gao et al. prospectively analyzed 362,193 participants from the UK Biobank and found that shorter sleep duration (≤ 7 h/d) was positively associated with IBS risk [10]. Santhi Swaroop Vege showed that shorter sleep duration was associated with the occurrence of IBS and frequent heartburn in a population-based study of 2,269 participants in Minnesota [32]. Yeliz et al. observed significantly lower scores in both sleep quality and quality-of-life metrics among adolescents with chronic gastritis compared to healthy controls [33]. One cohort study (Hunt study) conducted in Norway suggested a significantly increased risk of GERD symptoms in patients with insomnia disorder and that there was a bidirectional association [34]. Short sleep duration and poor sleep are associated risk factors for gastritis in a cross-sectional study [35]. Insomnia increases the risk of peptic ulcer in a MR study shows, while an association between sleep deprivation and inflammatory bowel disease (including Crohn's disease, ulcerative colitis and others) existed in well-designed cohort studies [36–38]. One study evaluating sleep and colorectal cancer showed that shorter sleep duration (< 6 h) increased an almost 50% increased risk of colorectal cancer [39]. Although these studies were rigorously designed and reported an association between insomnia and gastrointestinal disorders in observational studies, which are susceptible to confounders and measurement error. However, bidirectional MR analysis minimizes the effects of traditional bias using genetic variation as an instrumental variable to analyze causal associations based on a genetic perspective satisfying the three key assumptions [19], and we remove relevant outliers and outliers by detecting multiplicity, heterogeneity, and sensitivity through a variety of methods to make the results of assessment more reliable and stable. Therefore, the causal associations found by MR can provide new insights into the etiology of gastrointestinal diseases.
In this study, the results of genetically predicted insomnia demonstrated causal associations with four gastrointestinal disorders: GERD, IBS, chronic gastritis, and acute gastritis, which are consistent with previous studies. However, a causal association of insomnia with other gastrointestinal disorders was not detected since the potential confounders may distort the true association of insomnia with these disorders. Nowadays, the bidirectional association between insomnia and psychological disorders has been well established [40, 41], and psychological disorders are strongly associated with a variety of gastrointestinal disorders [42]. Insomnia was considered to induce gastrointestinal disorders through the gut-brain axis, which is a bidirectional network involving the central nervous system, autonomic nervous system, and enteric nervous system. Then, the brain increases the risk of disease by altering the state of gastrointestinal activity, permeability, fluid secretion, and gut microbiota [43, 44]. As the association, together with the complex mechanism, between sleep and the immune system have attached increasing importance and attention, showing that insomnia activates the cytokines IL-1, IL-6, and TNF to induce inflammation that plays an important role in the development of gastrointestinal disease [2]. Importantly, immune activation is closely related to the gut-brain axis, and there is bidirectional communication between central nervous system and immune system, and their joint action accelerate the diseases’ development [45].
As a complex and bidirectional stimulation, bidirectional MR analyses reveal complex genetic interplays between insomnia and gastrointestinal disorders, presenting both risk-enhancing and protective associations. While insomnia exhibits causal effects on GERD (OR = 1.86) and IBS (OR = 2.40), reverse analyses show chronic gastritis (OR = 0.98) confer reduced insomnia risk, that is, contrasting with acute gastritis's risk-increasing effect (OR = 1.014). This directional heterogeneity, particularly the paradoxical associations observed for chronic gastrointestinal conditions, necessitates large-scale, multi-population, and multi-center studies to enable profound elucidations. With regard to the strong interactions between insomnia and gastrointestinal disorders, it is even more far-reaching to emphasize the link from the clinical perspective; treating sleep largely prevents and improves gastrointestinal symptoms, and a healthier gastrointestinal tract can in turn improve sleep and greatly improve quality of life.
The two-sample MR analysis method in our study has the advantage of obtaining a larger sample size from published GWAS data, using multiple correlated SNPs as instrumental variables. To some extent, it improves the precision of causal association estimation and possesses an excellent causal detection power compared to single-sample MR [46]. Additionally, the samples were all from European populations, which minimized the problems of stratification bias and sample overlap. Most importantly, our study included several common gastrointestinal disorders and systematically characterized the bidirectional causal relationship between a variety of insomnia and gastrointestinal disorders, providing clues for the prevention and treatment of gastrointestinal disorders.
There are several limitations that need to be considered. Firstly, the insomnia data were derived from self-reports, which may divert from the actual situation. Secondly, although we tested for pleiotropy and excluded outliers using several methods, the problem of pleiotropy cannot be completely avoided, which is an inherent flaw of MR [47]. Last but not least, the results cannot be generalized to other populations since we mainly included European population samples.
In summary, our study provides genetic evidence for bidirectional causal relationships between insomnia and gastrointestinal disorders: insomnia elevates the risk of both IBS and GERD, while conversely, chronic gastritis demonstrates genetically proxied protective effects against insomnia development, which warrant further validations through large-scale studies. Importantly, acute gastritis exhibits risk-enhancing effects on insomnia susceptibility. We detected no robust causal association with the five gastrointestinal disorders. In our study, these insights advance etiological understandings and inform targeted prevention strategies for gastrointestinal pathology.
Supplementary Information
Acknowledgements
Summary-level data used in this paper related to the genetic of insomnia was published by Neale Lab, and outcome-related data was published by FinnGen, IIBDGC and Sakaue S et al., and downloaded from the Open GWAS database(https://gwas.mrcieu.ac.uk). The authors thank all investigators for sharing these data.
Authors’ contributions
JY analyzed the data, interpreted results and wrote the final paper. LJ and YG made critical revisions. ZW, YS and BC contributed to data collection. All authors contributed to the article and approved the submitted version.
Funding
This study was supported Local High-level University (cultivation) project in Shanghai (E1-2602–21-201006–6) and supported by Evaluation of Qingdao high-quality development (hospital) of demonstration projects.
Data availability
The data used in this study can be found in the Open GWAS database. The URL has been given in the Table 1.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Yongjin Guo, Email: yongjinguo11@outlook.com.
Liying Jiang, Email: j_meili@126.com.
References
- 1.Black CJ, Drossman DA, Talley NJ, Ruddy J, Ford AC. Functional gastrointestinal disorders: advances in understanding and management. Lancet. 2020;396(10263):1664–74. [DOI] [PubMed] [Google Scholar]
- 2.Khanijow V, Prakash P, Emsellem HA, Borum ML, Doman DB. Sleep dysfunction and gastrointestinal diseases. Gastroenterol Hepatol (N Y). 2015;11(12):817–25. [PMC free article] [PubMed] [Google Scholar]
- 3.Stern P. The many benefits of healthy sleep. Science. 2021;374(6567):550–1. [DOI] [PubMed] [Google Scholar]
- 4.Morin CM, Benca R. Chronic insomnia. Lancet. 2012;379(9821):1129–41. [DOI] [PubMed] [Google Scholar]
- 5.Roth T, Roehrs T. Insomnia: epidemiology, characteristics, and consequences. Clin Cornerstone. 2003;5(3):5–15. [DOI] [PubMed] [Google Scholar]
- 6.Yuan S, Mason AM, Burgess S, Larsson SC. Genetic liability to insomnia in relation to cardiovascular diseases: a Mendelian randomisation study. Eur J Epidemiol. 2021;36(4):393–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Huo Z, Ge F, Li C, Cheng H, Lu Y, Wang R, et al. Genetically predicted insomnia and lung cancer risk: a Mendelian randomization study. Sleep Med. 2021;87:183–90. [DOI] [PubMed] [Google Scholar]
- 8.Shu P, Ji L, Ping Z, Sun Z, Liu W. Association of insomnia and daytime sleepiness with low back pain: a bidirectional mendelian randomization analysis. Front Genet. 2022;13:938334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Huang J, Zuber V, Matthews PM, Elliott P, Tzoulaki J, Dehghan A. Sleep, major depressive disorder, and Alzheimer disease: A Mendelian randomization study. Neurology. 2020;95(14):e1963–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Gao X, Tian S, Huang N, Sun G, Huang T. Associations of daily sedentary behavior, physical activity, and sleep with irritable bowel syndrome: A prospective analysis of 362,193 participants. J Sport Health Sci 2023. [DOI] [PMC free article] [PubMed]
- 11.Graff LA, Vincent N, Walker JR, Clara I, Carr R, Ediger J, et al. A population-based study of fatigue and sleep difficulties in inflammatory bowel disease. Inflamm Bowel Dis. 2011;17(9):1882–9. [DOI] [PubMed] [Google Scholar]
- 12.Segawa K, Nakazawa S, Tsukamoto Y, Kurita Y, Goto H, Fukui A, Takano K. Peptic ulcer is prevalent among shift workers. Dig Dis Sci. 1987;32(5):449–53. [DOI] [PubMed] [Google Scholar]
- 13.Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Davies NM, Holmes MV, Davey SG. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362: k601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017;318(19):1925–6. [DOI] [PubMed] [Google Scholar]
- 16.Gupta V, Walia GK, Sachdeva MP. “Mendelian randomization”: an approach for exploring causal relations in epidemiology. Public Health. 2017;145:113–9. [DOI] [PubMed] [Google Scholar]
- 17.Wang J, Sui WN, Zhao YQ, Meng SY, Han WX, Ni J. Genetic evidence for the causal impact of insomnia on gastrointestinal diseases and the mediating effects of adiposity traits. J Gastroenterol Hepatol. 2024;39(11):2332–3233. [DOI] [PubMed] [Google Scholar]
- 18.张力攀, 蔡洪科. 失眠与肠易激综合征之间的孟德尔随机化研究[J]. 临床医学进展, 2025, 15(3): 940–946.
- 19.Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326(16):1614–21. [DOI] [PubMed] [Google Scholar]
- 20.Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey SG. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63. [DOI] [PubMed] [Google Scholar]
- 23.Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64. [DOI] [PubMed] [Google Scholar]
- 24.Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Chen M, Peng WY, Tang TC, Zheng H. Differential sleep traits have no causal effect on inflammatory bowel diseases: a mendelian randomization study. Front Pharmacol. 2021;12:763649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. 2019;48(3):713–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife 2018; 7. [DOI] [PMC free article] [PubMed]
- 31.Ohlsson B. Extraintestinal manifestations in irritable bowel syndrome: A systematic review. Therap Adv Gastroenterol. 2022;15:17562848221114558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Vege SS, Locke GR 3rd, Weaver AL, Farmer SA, Melton LJ 3rd, Talley NJ. Functional gastrointestinal disorders among people with sleep disturbances: a population-based study. Mayo Clin Proc. 2004;79(12):1501–6. [DOI] [PubMed] [Google Scholar]
- 33.Appak Y A , Zyurt G , Karakoyun M ,et al.Effects of Chronic Gastritis on Sleep and Quality of Life in Adolescents, The Journal of Pediatric Research, 2019, 6(4).
- 34.Lindam A, Ness-Jensen E, Jansson C, Nordenstedt H, Åkerstedt T, Hveem K, Lagergren J. Gastroesophageal reflux and sleep disturbances: a bidirectional association in a population-based Cohort Study. The HUNT Study Sleep. 2016;39(7):1421–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Feyisa ZT, Woldeamanuel BT. Prevalence and associated risk factors of gastritis among patients visiting Saint Paul Hospital Millennium Medical College, Addis Ababa, Ethiopia. PLoS ONE. 2021;16(2):e0246619. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Conley S, Jeon S, Lehner V, Proctor DD, Redeker NS. Sleep characteristics and rest-activity rhythms are associated with gastrointestinal symptoms among adults with inflammatory bowel disease. Dig Dis Sci. 2021;66(1):181–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Leal T, Gonçalves M, Antunes P, Costa D, Mendes S, Soares JB, et al. Sleep disturbance in inflammatory bowel disease is associated with disease activity and adverse outcome. Dig Dis. 2021;39(5):496–501. [DOI] [PubMed] [Google Scholar]
- 38.Zha LF, Dong JT, Wang JL, Chen QW, Wu JF, Zhou YC, et al. Effects of Insomnia on Peptic Ulcer Disease Using Mendelian Randomization. Oxid Med Cell Longev. 2021;2021:2216314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Thompson CL, Larkin EK, Patel S, Berger NA, Redline S, Li L. Short duration of sleep increases risk of colorectal adenoma. Cancer. 2011;117(4):841–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Fang H, Tu S, Sheng J, Shao A. Depression in sleep disturbance: a review on a bidirectional relationship, mechanisms and treatment. J Cell Mol Med. 2019;23(4):2324–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Gebara MA, Siripong N, DiNapoli EA, Maree RD, Germain A, Reynolds CF, et al. Effect of insomnia treatments on depression: a systematic review and meta-analysis. Depress Anxiety. 2018;35(8):717–31. [DOI] [PubMed] [Google Scholar]
- 42.Ruan X, Chen J, Sun Y, Zhang Y, Zhao J, Wang X, et al. Depression and 24 gastrointestinal diseases: a Mendelian randomization study. Transl Psychiatry. 2023;13(1):146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203–9. [PMC free article] [PubMed] [Google Scholar]
- 44.Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, et al. Irritable bowel syndrome. Nat Rev Dis Primers. 2016;2:16014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol. 2013;178(7):1177–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Sanderson E, Glymour MM, Holmes MV, Kang H, Morrison J, Munafò MR, et al. Mendelian randomization. Nat Rev Methods Primers 2022; 2. [DOI] [PMC free article] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data used in this study can be found in the Open GWAS database. The URL has been given in the Table 1.