Causal relationship between bipolar disorder and inflammatory bowel disease: A bidirectional two-sample mendelian randomization study
Open accessAbstract
Background: Growing evidence suggests a bidirectional association between bipolar disorder (BD) and inflammatory bowel disease (IBD); however, observational studies are prone to confounding, making causal inference and directional determination of these associations difficult. Methods: We performed bidirectional two-sample Mendelian randomization (MR) and selected single nucleotide polymorphisms (SNPs) associated with BD and IBD as instrumental variables (IV). SNPs and genetic associations with BD and IBD were obtained from the latest genome-wide association studies (GWAS) in Europeans (BD: cases/controls: 20352/31358; IBD: 12882/21770; Crohn’s disease (CD): 5,956/14927; ulcerative colitis (UC): 6968/20464). The inverse-variance-weighted method was the major method used in MR analyses. MR-Egger, weight mode, simple mode, and weighted median were used for quality control. Results: Genetically predicted BD (per log-odds ratio increase) was significantly positively associated with risk of IBD (OR: 1.18, 95% CI: 1.04–1.33), and UC (OR = 1.19, 95% CI: 1.05–1.35), but not CD (OR = 1.18, 95% CI: 0.95–1.48). The validation analysis found that combined OR of IBD, CD, and UC increased per log-OR of BD were 1.16(95% CI: 1.02–1.31), 1.20(95% CI: 0.98–1.48) 1.17(95% CI: 1.02–1.35), respectively. In contrast, no causal relationship was identified between genetically influenced IBD and BD. Conclusion: Our results confirm a causal relationship between BD and IBD, which may influence clinical decisions on the management of BD patients with intestinal symptoms. Although the reverse MR results did not support a causal effect of IBD on BD, the effect of the IBD active period on BD remains to be further investigated.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Wang et al. (2022) found a significant, positive association for genetically predicted bipolar disorder with the risk for IBD and ulcerative colitis (per log/odds ratio increase; odds ratios: 1.18 and 1.19, respectively).
“In 2022, Wang et al. found a significant, positive association for genetically predicted bipolar disorder with the risk for IBD and ulcerative colitis (per log/odds ratio increase; odds ratios: 1.18 and 1.19, respectively) [111].”
From Association between Childhood Onset Inflammatory Bowel Disease and Psychiatric Comorbidities in Adulthood (2023) · cites this paper as [111]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bowden, J., Davey Smith, G., & Burgess, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv080 · Cited by 9,816 · see citing works
Bowden, J., Davey Smith, G., Haycock, P. C., & Burgess, S. (2016) · Genetic Epidemiology · doi:10.1002/gepi.21965 · Cited by 8,922 · see citing works
Ng, S. C., Shi, H. Y., Hamidi, N., Underwood, F. E., Tang, W., Benchimol, E. I., Panaccione, R., Ghosh, S., Wu, J. C. Y., Chan, F. K. L., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32448-0 · Cited by 6,087 · see citing works
Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data
Burgess, S., Butterworth, A., & Thompson, S. G. (2013) · Genetic Epidemiology · doi:10.1002/gepi.21758 · Cited by 6,050 · see citing works
Avoiding bias from weak instruments in Mendelian randomization studies
Burgess, S., Thompson, S. G., & CRP CHD Genetics Collaboration (2011) · International Journal of Epidemiology · doi:10.1093/ije/dyr036 · Cited by 3,952 · see citing works
Emdin, C. A., Khera, A. V., & Kathiresan, S. (2017) · JAMA · doi:10.1001/jama.2017.17219 · Cited by 3,637 · see citing works
Cytokines in inflammatory bowel disease
Neurath, M. F. (2014) · Nature Reviews Immunology · doi:10.1038/nri3661 · Cited by 2,706 · see citing works
Orienting the causal relationship between imprecisely measured traits using GWAS summary data.
Hemani, G., Tilling, K., & Davey Smith, G. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1007081 · Cited by 2,607 · see citing works
Liu, J. Z., van Sommeren, S., Huang, H., Ng, S. C., Alberts, R., Takahashi, A., Ripke, S., Lee, J. C., Jostins, L., Shah, T., et al. (2015) · Nature Genetics · doi:10.1038/ng.3359 · Cited by 2,603 · see citing works
Lamb, C. A., Kennedy, N. A., Raine, T., Hendy, P. A., Smith, P. J., Limdi, J. K., Hayee, B., Lomer, M. C. E., Parkes, G. C., Selinger, C., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-318484 · Cited by 2,346 · see citing works
The Microbiome in Inflammatory Bowel Disease: Current Status and the Future Ahead
Kostic, A. D., Xavier, R. J., & Gevers, D. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.02.009 · Cited by 1,789 · see citing works
Epidemiology and risk factors for IBD
Ananthakrishnan, A. N. (2015) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2015.34 · Cited by 1,741 · see citing works
Genome-wide association study identifies 30 loci associated with bipolar disorder
eQTLGen Consortium, Stahl, E. A., BIOS Consortium, the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Breen, G., Forstner, A. J., McQuillin, A., Ripke, S., Trubetskoy, V., Mattheisen, M., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0397-8 · Cited by 1,519 · see citing works
de Lange, K. M., Moutsianas, L., Lee, J. C., Lamb, C. A., Luo, Y., Kennedy, N. A., Jostins, L., Rice, D. L., Gutierrez-Achury, J., Ji, S.-G., et al. (2017) · Nature Genetics · doi:10.1038/ng.3760 · Cited by 1,445 · see citing works
McIntyre, R. S., Berk, M., Brietzke, E., Goldstein, B. I., López-Jaramillo, C., Kessing, L. V., Malhi, G. S., Nierenberg, A. A., Rosenblat, J. D., Majeed, A., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31544-0 · Cited by 1,047 · see citing works
Mechanisms of Disease: Inflammatory Bowel Diseases
Ramos, G. P., & Papadakis, K. A. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.09.013 · Cited by 1,045 · see citing works
Vieta, E., Berk, M., Schulze, T. G., Carvalho, A. F., Suppes, T., Calabrese, J. R., Gao, K., Miskowiak, K. W., & Grande, I. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.8 · Cited by 891 · see citing works
Bowden, J., Spiller, W., Del Greco M, F., Sheehan, N., Thompson, J., Minelli, C., & Davey Smith, G. (2018) · International Journal of Epidemiology · doi:10.1093/ije/dyy101 · Cited by 880 · see citing works
Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses
Piovani, D., Danese, S., Peyrin‐Biroulet, L., Nikolopoulos, G. K., Lytras, T., & Bonovas, S. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.04.016 · Cited by 788 · see citing works
Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease
Friedrich, M., Pohin, M., & Powrie, F. M. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.017 · Cited by 750 · see citing works
Brain–Gut Interactions in Inflammatory Bowel Disease
Bonaz, B. L., & Bernstein, C. N. (2013) · Gastroenterology · doi:10.1053/j.gastro.2012.10.003 · Cited by 667 · see citing works
Cytokine Alterations in Bipolar Disorder: A Meta-Analysis of 30 Studies
Modabbernia, A., Taslimi, S., Brietzke, E., & Ashrafi, M. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.007 · Cited by 596 · see citing works
The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013
Ferrari, A. J., Stockings, E., Khoo, J., Erskine, H. E., Degenhardt, L., Vos, T., & Whiteford, H. A. (2016) · Bipolar Disorders · doi:10.1111/bdi.12423 · Cited by 583 · see citing works
Liu, R. T., Walsh, R. F. L., & Sheehan, A. E. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.03.023 · Cited by 564 · see citing works
The Gut–Brain Axis and the Microbiome: Mechanisms and Clinical Implications
Osadchiy, V., Martin, C. R., & Mayer, E. A. (2019) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2018.10.002 · Cited by 555 · see citing works
Lammers, K. M., Lu, R., Brownley, J., Lu, B., Gerard, C. J., Thomas, K., Rallabhandi, P., Shea‐Donohue, T., Tamiz, A. P., Alkan, Ş. Ş., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.023 · Cited by 545 · see citing works
Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2
Tripathi, A. K., Lammers, K. M., Goldblum, S. E., Shea‐Donohue, T., Netzel–Arnett, S., Buzza, M. S., Antalis, T., Vogel, S. N., Zhao, A., Yang, S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906773106 · Cited by 449 · see citing works
Walker, J. R., Ediger, J. P., Graff, L. A., Greenfeld, J. M., Clara, I., Lix, L., Rawsthorne, P., Miller, N., Rogala, L., McPhail, C. M., et al. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2008.01980.x · Cited by 437 · see citing works
Cytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis
Munkholm, K., Braüner, J. V., Kessing, L. V., & Vinberg, M. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.05.018 · Cited by 402 · see citing works
Gracie, D. J., Hamlin, P. J., & Ford, A. C. (2019) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(19)30089-5 · Cited by 358 · see citing works
Peeters, M., Joossens, S. B. A., Vermeire, S., VLIETINCK, R. F., Bossuyt, X., & Rutgeerts, P. J. (2001) · The American Journal of Gastroenterology · doi:10.1016/s0002-9270(00)02406-0 · Cited by 341 · see citing works
Porcu, E., Rüeger, S., Lepik, K., eQTLGen Consortium, Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Arindrarto, W., Awadalla, P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10936-0 · Cited by 322 · see citing works
Peeters, M., Joossens, S. B. A., Vermeire, S. A. R. A., et al. (2001) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2001.03613.x · Cited by 301 · see citing works
Davey Smith, G., Holmes, M. V., Davies, N. M., & Ebrahim, S. (2020) · European Journal of Epidemiology · doi:10.1007/s10654-020-00622-7 · Cited by 287 · see citing works
Increased burden of psychiatric disorders in inflammatory bowel disease
Bernstein, C. N., Hitchon, C. A., Walld, R., Bolton, J. M., Sareen, J., Walker, J. R., Graff, L. A., Patten, S. B., Singer, A., Lix, L. M., et al. (2019) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izy235 · Cited by 274 · see citing works
Autoimmune diseases, bipolar disorder, and non-affective psychosis
Eaton, W. W., Pedersen, M. G., Nielsen, P. R., & Mortensen, P. B. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00853.x · Cited by 262 · see citing works
Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat
Santos, J., Saunders, P. R., Hanssen, N. P. M., Yang, P., Yates, D. A., Groot, J. A., & Perdue, M. H. (1999) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.1999.277.2.g391 · Cited by 251 · see citing works
Zhao, Q., Chen, Y., Wang, J., & Small, D. S. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz142 · Cited by 188 · see citing works
Berre, C. L., Peyrin‐Biroulet, L., Sandborn, W. J., Colombel, J., Rubin, D. T., Chowers, Y., Reinisch, W., Schreiber, S., Allez, M., D’Haens, G., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.10.065 · Cited by 177 · see citing works
Hope, S., Dieset, I., Agartz, I., Steen, N. E., Ueland, T., Melle, I., Aukrust, P., & Andreassen, O. A. (2011) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.08.003 · Cited by 164 · cited 1× · see citing works
“Another study found that sTNF-R1, IL-1Ra, OPG, and IL-6 were significantly altered in the affective state and that they correlated with the severity of affective symptoms in BD patients (Hope et al. 2011).”
BackgroundDepression and Inflammatory Bowel Disease: A Bidirectional Two-sample Mendelian Randomization Study
Luo, J. M., Xu, Z., Noordam, R., van Heemst, D., & Li‐Gao, R. (2021) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjab191 · Cited by 155 · see citing works
Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease
Marrie, R. A., Walld, R., Bolton, J. M., Sareen, J., Walker, J. R., Patten, S. B., Singer, A., Lix, L. M., Hitchon, C. A., El-Gabalawy, R., et al. (2019) · Epidemiology and Psychiatric Sciences · doi:10.1017/s2045796017000579 · Cited by 144 · see citing works
Smith, D. J., Martin, D., McLean, G., Langan, J., Guthrie, B., & Mercer, S. W. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-263 · Cited by 138 · see citing works
The Brain-Gut Axis: Psychological Functioning and Inflammatory Bowel Diseases
Peppas, S., Pansieri, C., Piovani, D., Danese, S., Peyrin‐Biroulet, L., Tsantes, A. G., Brunetta, E., Tsantes, A. Ε., & Bonovas, S. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030377 · Cited by 114 · see citing works
Nikolova, V., Cleare, A., Young, A., & Stone, J. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040647 · Cited by 106 · see citing works
Heightened Responses to Stressors in Patients with Inflammatory Bowel Disease
Farhadi, A., Keshavarzian, A., de Kar, L. D. V., Jakate, S. M., Domm, A., Zhang, L., Shaikh, M. W., Banan, A., & Fields, J. Z. (2005) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.50071.x · Cited by 83 · see citing works
Severance, E. G., Gressitt, K. L., Yang, S., Stallings, C. R., Origoni, A. E., Vaughan, C., Khushalani, S., Alaedini, A., Dickerson, F., & Yolken, R. H. (2013) · Bipolar Disorders · doi:10.1111/bdi.12159 · Cited by 79 · see citing works
Nikolova, V. L., Pelton, L., Moulton, C. D., Zorzato, D., Cleare, A. J., Young, A. H., & Stone, J. M. (2022) · Psychosomatic Medicine · doi:10.1097/psy.0000000000001046 · Cited by 42 · see citing works
Inflammatory bowel disease and bipolar disorder: A population-based cross-sectional study
Kao, L.-T., Lin, H.-C., & Lee, H.-C. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.01.014 · Cited by 36 · see citing works
Immune activation by casein dietary antigens in bipolar disorder
Severance, E. G., Dupont, D., Dickerson, F., Stallings, C. R., Origoni, A. E., Krivogorsky, B., Yang, S., Haasnoot, W., & Yolken, R. H. (2010) · Bipolar Disorders · doi:10.1111/j.1399-5618.2010.00879.x · Cited by 34 · see citing works
Corticotropin-releasing factor: A possible key to gut dysfunction in the critically ill
Hill, L. T., Kidson, S. H., & Michell, W. L. (2013) · Nutrition · doi:10.1016/j.nut.2012.12.023 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sălcudean, A., Nan, A. G., Bodo, C. R., Cosma, M. C., Strete, E. G., & Lica, M. M. (2023) · Diagnostics · doi:10.3390/diagnostics13111868 · Cited by 24 · see citing works
Lin, S.-K. K., Chen, H., Chen, I., Hsu, C.-D., Huang, M., Liu, C., Wu, S., Chen, P., Chen, C.-H., & Kuo, P. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03521-1 · Cited by 27 · see citing works
Yang, X., Yang, L., Zhang, T., Zhang, H., Chen, H., & Zuo, X. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1267834 · Cited by 18 · see citing works
Immune dysregulation in bipolar disorder
Argue, B. M., Casten, L. G., McCool, S., Alrfooh, A., Richards, J. G., Wemmie, J. A., Magnotta, V. A., Williams, A. J., Michaelson, J. J., Fiedorowicz, J. G., et al. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.01.062 · Cited by 14 · see citing works
Han, X., Lin, X., Li, G., Wang, J., Meng, X., Chen, T., Zhang, Y., & Fu, X. (2024) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2024.111806 · Cited by 13 · see citing works
Wang, B.-R., Wang, J., Tian, T., Zhang, S., Zhao, Y.-Q., Meng, S., Wu, Z.-Y., Huang, F., Zeng, J., & Ni, J. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.12.042 · Cited by 6 · see citing works
Peripheral inflammation is associated with impaired sadness recognition in euthymic bipolar patients
Chang, C.-Y., Chang, H. H., Wu, C. Y., Tsai, Y. T., Lu, T., Chang, W. H., Hsu, C., Chen, P. S., & Tseng, H. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.03.049 · Cited by 4 · see citing works
Guo, Z., Xu, C., Fang, Z., Yu, X., Yang, K. G., Liu, C., Ning, X., Dong, Z., & Liu, C. (2024) · Medicine · doi:10.1097/md.0000000000038392 · Cited by 3 · see citing works
You, T., Yang, X., Feng, H., Liu, Z., Chen, C., & Qiu, J. (2025) · Medicine · doi:10.1097/md.0000000000046691
Muhammad, Y. A. (2026) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2026.1775109
- Authors
- Wang, Z., Wang, X., Zhao, X., Hu, Z., Sun, D., Wu, D., & Xing, Y.
- Affiliations
- First Hospital of China Medical University (CN)
- Corresponding author
- Xing, Yanan
- Venue
- Frontiers in Genetics
- Publisher
- Frontiers Media SA
- Published
- 2022-09-20
- Volume
- 13
- Pages
- 970933-970933
- ISSN
- 1664-8021 (ISSN-L)
- PMC
- PMC9531165
- OpenAlex
- W4296664621
- Cited by
- 10
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 3
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- bipolar disorder, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bidirectional causality, genetic risk factors, causal inference
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
