Welcome to visit Zhongnan Medical Journal Press Series journal website!

Research progress on Mendelian randomization for exploring the pathogenesis and precision therapy of inflammatory bowel disease

Published on Oct. 30, 2026Total Views: 20 timesTotal Downloads: 9 timesDownloadMobile

Author: SHEN Junji 1 XU Yichuan 2 LIN Jiang 2 QIAN Yiming 1

Affiliation: 1.Department of Emergency Medicine, Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China 2.Department of Gastroenterology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China

Keywords: Inflammatory bowel disease Genome-wide association study Mendelian randomization Risk factors

DOI: 10.12173/j.issn.1004-5511.202601112

Reference: Shen JJ, Xu YC, Lin J, et al. Research progress on Mendelian randomization for exploring the pathogenesis and precision therapy of inflammatory bowel disease[J]. Yixue Xinzhi Zazhi, 2026, 36(10): 1175-1182. DOI: 10.12173/j.issn.1004-5511.202601112.[Article in Chinese]

  • Abstract
  • Full-text
  • References
Abstract

The pathogenesis of inflammatory bowel disease (IBD) is complex, and traditional observational studies cannot easily avoid confounding factors to establish robust causal relationships. As an emerging genetic analytical approach, Mendelian randomization(MR) uses genetic variations as instrumental variables, which provides a novel perspective for exploring the etiology and pathogenesis of IBD. This review systematically summarizes research progress on MR in exploring the pathogenesis and precision therapy of IBD, and focuses on the role of MR in identifying environmental risk factors for IBD, elucidating pathogenesis, clarifying comorbid associations, and exploring therapeutic targets, to provide crucial evidence for elucidating disease characteristics and open new research pathways for drug development and precision therapy.

Full-text
Please download the PDF version to read the full text: download
References

1. BrunerLP, WhiteAM, ProksellS. Inflammatory bowel disease[J]. Prim Care, 2023, 50(3): 411-427. doi:10.1016/j.pop.2023.03.009

2. DunleavyKA, RaffalsLE, CamilleriM. Intestinal barrier dysfunction in inflammatory bowel disease: underpinning pathogenesis and therapeutics[J]. Dig Dis Sci, 2023, 68(12): 4306-4320. doi:10.1007/s10620-023-08122-w

3. SinghN, BernsteinCN. Environmental risk factors for inflammatory bowel disease[J]. United European Gastroenterol J, 2022, 10(10): 1047-1053. doi:10.1002/ueg2.12319

4. XvY, ChenJ, LinJ. Gut microbiota and functional dyspepsia: a two-sample Mendelian randomization study[J]. Front Microbiol, 2024, 15: 1377392. doi:10.3389/fmicb.2024.1377392

5. LarssonSC, ButterworthAS, BurgessS. Mendelian randomization for cardiovascular diseases: principles and applications[J]. Eur Heart J, 2023, 44(47): 4913-4924. doi:10.1093/eurheartj/ehad736

6. SandersonE, GlymourMM, HolmesMV, et al. Mendelian randomization[J]. Nat Rev Methods Primers, 2022, 2(1): 6. doi:10.1038/s43586-021-00092-5

7. XueH, ShenX, PanW. Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects[J]. Am J Hum Genet, 2021, 108(7): 1251-1269. doi:10.1016/j.ajhg.2021.05.014

8. LiuZ, LiuR, GaoH, et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries[J]. Nat Genet, 2023, 55(5): 796-806.

9. GargM, KarpinskiM, MatelskaD, et al. Disease prediction with multi-omics and biomarkers empowers case-control genetic discoveries in the UK Biobank[J]. Nat Genet, 2024, 56(9): 1821-1831. doi:10.1038/s41588-024-01898-1

10. KurkiMI, KarjalainenJ, PaltaP, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518.

11. WangJ, KurilshikovA, RadjabzadehD, et al. Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative[J]. Microbiome, 2018, 6(1): 101. doi:10.1186/s40168-018-0479-3

12. VõsaU, ClaringbouldA, WestraHJ, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression[J]. Nat Genet, 2021, 53(9): 1300-1310. doi:10.1038/s41588-021-00913-z

13. PiovaniD, DaneseS, Peyrin-BirouletL, et al. Environmental risk factors for inflammatory bowel diseases: an umbrella review of Meta-analyses[J]. Gastroenterology, 2019, 157(3): 647-659.e4. doi:10.1053/j.gastro.2019.04.016

14. ZhangH, KallaR, ChenJ, et al. Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease[J]. Nat Commun, 2024, 15(1): 595. doi:10.1038/s41467-024-44841-y

15. MageeEA, EdmondLM, TaskerSM, et al. Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis[J]. Nutr J, 2005, 4: 7. doi:10.1186/1475-2891-4-7

16. NieJY, ZhaoQ. Beverage consumption and risk of ulcerative colitis: systematic review and Meta-analysis of epidemiological studies[J]. Medicine (Baltimore), 2017, 96(49): e9070. doi:10.1097/md.0000000000009070

17. GeorgiouAN, NtritsosG, PapadimitriouN, et al. Cigarette smoking, coffee consumption, alcohol intake, and risk of Crohn's disease and ulcerative colitis: a Mendelian randomization study[J]. Inflamm Bowel Dis, 2021, 19(2): 162-168. doi:10.1093/ibd/izaa152

18. ChenJ, RuanX, FuT, et al. Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from Mendelian randomization analysis[J]. EBioMedicine, 2024, 103: 105110. doi:10.1016/j.ebiom.2024.105110

19. ChenJ, RuanX, YuanS, et al. Antioxidants, minerals and vitamins in relation to Crohn's disease and ulcerative colitis: a Mendelian randomization study[J]. Aliment Pharmacol Ther, 2023, 57(4): 399-408. doi:10.1111/apt.17392

20. LinZ, LuoW, ZhangK, et al. Environmental and microbial factors in inflammatory bowel disease model establishment: a review partly through Mendelian randomization[J]. Gut Liver, 2024, 15(3): 370-390. doi:10.5009/gnl230179

21. ChenJ, ZhangH, FuT, et al. Exposure to air pollution increases susceptibility to ulcerative colitis through epigenetic alterations in CXCR2 and MHC class Ⅲ region[J]. EBioMedicine, 2024, 110: 105443. doi:10.1016/j.ebiom.2024.105443

22. TaoH, YuZ, DongY, et al. Lipids, lipid-lowering agents, and inflammatory bowel disease: a Mendelian randomization study[J]. Front Immunol, 2023, 14: 1160312. doi:10.3389/fimmu.2023.1160312

23. YuF, DuY, LiC, et al. Association between metabolites in tryptophan-kynurenine pathway and inflammatory bowel disease: a two-sample Mendelian randomization[J]. Sci Rep, 2024, 14(1): 201. doi:10.1038/s41598-023-50990-9

24. AstoreC, NagpalS, GibsonG. Mendelian randomization indicates a causal role for omega-3 fatty acids in inflammatory bowel disease[J]. Int J Mol Sci, 2022, 23(22): 14380. doi:10.3390/ijms232214380

25. LiZ, JiaL, HuaiS. Circulating inflammatory proteins mediate the causal effect of gut microbiota on inflammatory bowel disease: Bayesian and mediated Mendelian randomization[J]. FASEB Bioadv, 2025, 7(7): e70039. doi:10.1096/fba.2025-00114

26. ZhaoW, LiS, LiQ, et al. Mendelian randomization reveals predictive, preventive, and personalized insights into inflammatory bowel disease: the role of gut microbiome and circulating inflammatory proteins[J]. EPMA J, 2024, 15(4): 693-709. doi:10.1007/s13167-024-00384-2

27. GreuterT, RiederF, KucharzikT, et al. Emerging treatment options for extraintestinal manifestations in IBD[J]. Gut, 2021, 70(4): 796-802. doi:10.1136/gutjnl-2020-322129

28. FanX, HeA, LiK, et al. The causal impact of genetically predicted inflammatory bowel disease on extraintestinal manifestations: a Mendelian randomization study[J]. BMC Gastroenterol, 2025, 25(1): 135. doi:10.1186/s12876-024-03566-4

29. ChenY, ZhangHH, LuYX, et al. Genetic architecture of primary sclerosing cholangitis: shared pathways with inflammatory bowel disease and gut-liver axis mediation[J]. Int J Surg, 2025, 112(1): 629-642. doi:10.1097/js9.0000000000003594

30. ZhouS, ZiJ, HuY, et al. Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal tract disorders[J]. J Affect Disord, 2025, 374: 84-90. doi:10.1016/j.jad.2025.01.048

31. ZengR, WangJ, JiangR, et al. Investigating causality and shared genetic architecture between neurodegenerative disorders and inflammatory bowel disease[J]. Aging Dis, 2023, 14(4): 1349-1359.

32. LiF, ZhaoQ, TangT, et al. Brain imaging derived phenotypes: a biomarker for the onset of inflammatory bowel disease and a potential mediator of mental complications[J]. Front Immunol, 2024, 15: 1359540. doi:10.3389/fimmu.2024.1359540

33. JessT, JensenBW, AnderssonM, et al. Inflammatory bowel diseases increase risk of type 2 diabetes in a nationwide cohort study[J]. Clin Gastroenterol Hepatol, 2020, 18(4): 881-888.e1. doi:10.1016/j.cgh.2019.07.052

34. XiaoX, WuX, YiL, et al. Causal linkage between type 2 diabetes mellitus and inflammatory bowel disease: an integrated Mendelian randomization study and bioinformatics analysis[J]. Front Endocrinol (Lausanne), 2024, 15: 1275699. doi:10.3389/fendo.2024.1275699

35. CaiY, XieS, JiaX, et al. Integrated analysis of Mendelian randomization and Bayesian colocalization reveals bidirectional causal association between inflammatory bowel disease and psoriasis[J]. Ann Med, 2023, 55(2): 2281658. doi:10.1080/07853890.2023.2281658

36. LiH, TangD, LiuY, et al. A multitrait analysis of genome-wide association study reveals the shared genetic architecture between inflammatory bowel disease and ankylosing spondylitis[J]. Mediators Inflamm, 2025, 2025: 4012195. doi:10.1155/mi/4012195

37. YangY, MuscoH, Simpson-YapS, et al. Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases[J]. Nat Commun, 2021, 12(1): 5641. doi:10.1038/s41467-021-25768-0

38. GagnonE, ArsenaultBJ. Leveraging drug-target Mendelian randomization for tailored lipoprotein-lipid lowering[J]. Curr Opin Lipidol, 2025, 36(2): 71-77. doi:10.1097/mol.0000000000000977

39. ParisinosCA, SerghiouS, KatsoulisM, et al. Variation in interleukin 6 receptor gene associates with risk of Crohn's disease and ulcerative colitis[J]. Gastroenterology, 2018, 155(2): 303-306.e2. doi:10.1053/j.gastro.2018.05.022

40. HolmstroemRB, NielsenOH, JacobsenS, et al. COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis[J]. J Immunother Cancer, 2022, 10(9): e005111. doi:10.1136/jitc-2022-005111

41. PetitpainN, D'AmicoF, Yelehe-OkoumaM, et al. IL-17 inhibitors and inflammatory bowel diseases: a postmarketing study in Vigibase[J]. Clin Pharmacol Ther, 2021, 110(1): 159-168. doi:10.1002/cpt.2155

42. CaiY, JiaX, XuLet al. Interleukin-17 and inflammatory bowel disease: a 2-sample Mendelian randomization study[J]. Front Immunol, 2023, 14: 1238457. doi:10.3389/fimmu.2023.1238457

43. MiJ, LiuZ, PeiS, et al. Mendelian randomization study for the roles of IL-18 and IL-1 receptor antagonist in the development of inflammatory bowel disease[J]. Int Immunopharmacol, 2022, 110: 109020. doi:10.1016/j.intimp.2022.109020

44. WilliamsMA, O'CallaghanA, CorrSC. IL-33 and IL-18 in inflammatory bowel disease etiology and microbial interactions[J]. Front Immunol, 2019, 10: 1091. doi:10.3389/fimmu.2019.01091

45. ZhangX, ZhaoH, WanM, et al. Associations of 2923 plasma proteins with incident inflammatory bowel disease in a prospective cohort study and genetic analysis[J]. Nat Commun, 2025, 16(1): 2813. doi:10.1038/s41467-025-57879-3

46. BergemalmD, AnderssonE, HultdinJ, et al. Systemic inflammation in preclinical ulcerative colitis[J]. Gastroenterology, 2021, 161(5): 1526-1539.e9. doi:10.1053/j.gastro.2021.07.026

47. ChenJ, XuF, RuanX, et al. Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses[J]. EBioMedicine, 2023, 89: 104494. doi:10.1016/j.ebiom.2023.104494

48. ChenJ, RuanX, SunY, et al. Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease[J]. EBioMedicine, 2024, 99: 104934. doi:10.1016/j.ebiom.2023.104934

49. PapD, Veres-SzékelyA, SzebeniB, et al. PARK7/DJ-1 as a therapeutic target in gut-brain axis diseases[J]. Int J Mol Sci, 2022, 14(23): 6626.

50. Gwyer FindlayE, SuttonG, HoGT. The MARVEL trial: a phase 2b randomised placebo-controlled trial of oral MitoQ in moderate ulcerative colitis[J]. Immunother Adv, 2020, 12(1): ltaa002. doi:10.1093/immadv/ltaa002

51. YangJ, HuangY, WangZ, et al. A PheWAS approach to identify associations of GBA1 variants with comprehensive phenotypes beyond neurological diseases[J]. NPJ Parkinsons Dis, 2025, 11(1): 48. doi:10.1038/s41531-025-00901-8

52. DeT, ZhangH, AlarconC, et al. Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease[J]. Pharmacogenet Genomics, 2022, 32(1): 1-9. doi:10.1097/fpc.0000000000000445

53. YazarS, Alquicira-HernandezJ, WingK, et al. Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease[J]. Science, 2022, 376(6589): eabf3041. doi:10.1126/science.abf3041

Popular Papers