AccScience Publishing / JCBP / Online First / DOI: 10.36922/JCBP025060010
Submit to JCBP
Cite this article
2
Download
28
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Causal association between constipation and white matter microstructure: A Mendelian randomization study

Cong Zhou1,2 ,  Hailong Shen1 ,  Shanling Ji1 ,  Shengbo Han2 ,  Zhengyang Chang4 ,  Hao Yu1 ,  Mingfeng Fan5 ,  Yongming Huang5 ,  Ruiqing Wang6 ,  Sen Li1* ,  Shuai Wang5*
Show Less
1 School of Mental Health, Jining Medical University, Jining, Shandong, China
2 Department of Psychology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
3 School of Clinical Medicine, Jining Medical University, Jining, Shandong, China
4 College of Integrated Traditional Chinese and Western Medicine, Jining Medical University, Jining, Shandong, China
5 Department of Anorectal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
6 Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
JCBP, 025060010 https://doi.org/10.36922/JCBP025060010
Received: 7 February 2025 | Revised: 12 March 2025 | Accepted: 16 May 2025 | Published online: 5 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Constipation, a prevalent gastrointestinal issue, has been linked to neurological health through the gut–brain axis (GBA). This study investigated the genetic association between constipation and white matter (WM) microstructure using a two-sample bidirectional Mendelian randomization (MR) approach. Genetic instruments for constipation were derived from the FinnGen study (41,124 cases and 371,057 controls). Summary statistics for diffusion tensor imaging parameters, including fractional anisotropy (FA) and mean diffusivity (MD), were obtained from the UK Biobank (33,292 subjects). The primary MR analysis used the inverse variance weighted (IVW) method, with supplementary analyses including weighted median, constrained maximum likelihood, and robust adjusted profile score methods. Sensitivity analyses, including Cochran’s Q test and MR-Egger regression, assessed heterogeneity and pleiotropy. Two WM imaging-derived phenotypes showed significant causal associations with constipation. Specifically, a higher second MD principal component of the superior longitudinal fasciculus (SLF) showed a significant protective effect against constipation (odds ratio [OR]=0.71, 95% confidence interval [CI]=0.58 – 0.87, p=7.55×10−4). Conversely, higher FA in the anterior corona radiata (ACR) increased constipation risk (OR=1.33, 95% CI=1.11 – 1.60, p=2.13×10−3). No significant causal effect of constipation on WM microstructure was found. All supplementary analyses corroborated the IVW results, indicating robustness and consistency. Sensitivity analyses showed low heterogeneity and no significant directional pleiotropy. This study provides strong evidence for a genetic association between specific WM microstructures and constipation, emphasizing the role of the SLF and ACR in the GBA. These findings highlight the need to consider neurological factors in understanding and managing constipation and warrant further research into the underlying mechanisms and broader implications of the GBA.

Keywords
Constipation
White matter
Diffusion tensor imaging
Mendelian randomization
Gut-brain axis
Funding
This research was funded by the Medical and Health Science and Technology Development Plan of Shandong Province (Grant No.: 202003061210 and 202304011343), the Key Research and Development Plan of Jining City (Grant No.: 2021YXNS024 and 2023JNZC141), the Cultivation Plan of High-level Scientific Research Projects of Jining Medical University (Grant No.: JYGC2021KJ006), the Ministry of Education’s Industry School Cooperation Collaborative Education Project (Grant No.: 220900242232529), the National Natural Science Foundation of China (81901358), the Natural Science Foundation of Shandong Province (Grant No.: ZR2019BH001 and ZR2021YQ55), the Young Taishan Scholars of Shandong Province (Grant No.: tsqn201909146), and the Supporting Fund for Teachers’ Research of Jining Medical University (Grant No.: 600903001).
Conflict of interest
The authors declare no competing interests.
References
  1. Morais LH, Schreiber HL 4th, Mazmanian S. The gut microbiota-brain axis in behaviour and brain disorders. Nat Rev Microbiol. 2021;19(4):241-255. doi: 10.1038/s41579-020-00460-0

 

  1. Black CJ, Drossman DA, Talley NJ, Ruddy J, Ford AC. Functional gastrointestinal disorders: Advances in understanding and management. Lancet. 2020;396(10263):1664-1674. doi: 10.1016/s0140-6736(20)32115-2

 

  1. Mayer EA, Nance K, Chen S. The gut-brain axis. Annu Rev Med. 2022;73(1):439-453. doi: 10.1146/annurev-med-042320-014032

 

  1. Marilia C, Annunziata S, Maria Antonietta M, Carola S. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209.

 

  1. Le Bihan D, Mangin JF, Poupon C, et al. Diffusion tensor imaging: Concepts and applications. J Magn Reson Imaging. 2001;13(4):534-546. doi: 10.1002/jmri.1076

 

  1. Lebel C, Deoni S. The development of brain white matter microstructure. Neuroimage. 2018;182:207-218. doi: 10.1016/j.neuroimage.2017.12.097

 

  1. Setiadi TM, Martens S, Opmeer EM, et al. Widespread white matter aberration is associated with the severity of apathy in amnestic mild cognitive impairment: Tract-based spatial statistics analysis. Neuroimage Clin. 2021;29:102567. doi: 1016/j.nicl.2021.102567

 

  1. Mitelman SA. Transdiagnostic neuroimaging in psychiatry: A review. Psychiatry Res. 2019;277:23-38. doi: 10.1016/j.psychres.2019.01.026

 

  1. Ellingson BM, Mayer E, Harris RJ, et al. Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome. Pain. 2013;154(9):1528-1541. doi: 10.1016/j.pain.2013.04.010

 

  1. Hu Y, Jia Z, Zhang L, et al. White-matter microstructural alterations in patients with functional constipation: A tract-based spatial statistics study. Neurogastroenterol Motil. 2022;34(5):e14338. doi: 10.1111/nmo.14338

 

  1. 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):304-314. doi: 10.1002/gepi.21965

 

  1. Smith GD, Ebrahim S. ‘Mendelian randomization’: Can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22. doi: 10.1093/ije/dyg070

 

  1. Davey Smith G, Hemani G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23:R89-R98. doi: 10.1093/hmg/ddu328

 

  1. Jiang L, Li JC, Shen L, Tang BS, Guo JF. Association between inflammatory bowel disease and Alzheimer’s disease: Multivariable and bidirectional Mendelian randomisation analyses. Gut. 2023;72(9):1797-1799. doi: 10.1136/gutjnl-2022-327860

 

  1. Lu L, Liu C, Liu K, et al. The causal effects of leisure screen time on irritable bowel syndrome risk from a Mendelian randomization study. Sci Rep. 2023;13(1):13216. doi: 10.1038/s41598-023-40153-1

 

  1. Sun D, Zhang Y, Wang R, et al. Causal effects of gut microbiota on multiple sclerosis: A two-sample mendelian randomization study. Brain Behav. 2024;14(6):e3593. doi: 10.1002/brb3.3593

 

  1. Gong W, Guo P, Li Y, et al. Role of the gut-brain axis in the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders: A genome-wide pleiotropic analysis. JAMA Psychiatry. 2023;80(4):360-370. doi: 10.1001/jamapsychiatry.2022.4974

 

  1. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613(7944):508-518. doi: 10.1038/s41586-022-05473-8

 

  1. Zhao B, Li T, Yang Y, et al. Common genetic variation influencing human white matter microstructure. Science. 2021;372(6548):eabf3736. doi: 10.1126/science.abf3736

 

  1. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658-665. doi: 10.1002/gepi.21758

 

  1. Slob EAW, Burgess S. A comparison of robust mendelian randomization methods using summary data. Genet Epidemiol. 2020;44(4):313-329. doi: 10.1002/gepi.22295

 

  1. Douglas Fields R. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7):361-370. doi: 10.1016/j.tins.2008.04.001

 

  1. Peter JB, Derek KJ. Diffusion-tensor MRI: Theory, experimental design and data analysis - a technical review. NMR Biomed. 2002;15:456-467. doi: 10.1002/nbm.783

 

  1. Nakajima R, Kinoshita M, Shinohara H, Nakada M. The superior longitudinal fascicle: reconsidering the fronto-parietal neural network based on anatomy and function. Brain Imaging Behav. 2020;14(6):2817-2830. doi: 10.1007/s11682-019-00187-4

 

  1. Wassenaar TM, Yaffe K, Van Der Werf YD, Sexton CE. Associations between modifiable risk factors and white matter of the aging brain: Insights from diffusion tensor imaging studies. Neurobiol Aging. 2019;80:56-70. doi: 10.1016/j.neurobiolaging.2019.04.006

 

  1. Sanjuan PM, Thoma R, Claus ED, Mays N, Caprihan A. Reduced white matter integrity in the cingulum and anterior corona radiata in posttraumatic stress disorder in male combat veterans: A diffusion tensor imaging study. Psychiatry Res. 2013;214(3):260-268. doi: 10.1016/j.pscychresns.2013.09.002

 

  1. Burke T, Holleran L, Mothersill D, et al. Bilateral anterior corona radiata microstructure organisation relates to impaired social cognition in schizophrenia. Schizophr Res. 2023;262:87-94. doi: 10.1016/j.schres.2023.10.035

 

  1. Aburto MR, Cryan JF. Gastrointestinal and brain barriers: Unlocking gates of communication across the microbiota-gut-brain axis. Nat Rev Gastroenterol Hepatol. 2024;21(4):222-247. doi: 10.1038/s41575-023-00890-0

 

  1. McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356-369. doi: 10.1038/nrg2344

 

  1. Ting Q, Liyang S, Yazhou G, Chang C, Jian Y. From genetic associations to genes: Methods, applications, and challenges. Trends Genet. 2024;40:642-667. doi: 10.1016/j.tig.2024.04.008

 

  1. Zhao B, Zhang J, Ibrahim JG, et al. Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n = 17,706). Mol Psychiatry. 2021;26(8):3943-3955. doi: 10.1038/s41380-019-0569-z

 

  1. Tae WS, Ham BJ, Pyun SB, Kang SH, Kim BJ. Current clinical applications of diffusion-tensor imaging in neurological disorders. J Clin Neurol. 2018;14(2):129-140. doi: 10.3988/jcn.2018.14.2.129

 

  1. Konrad JK, Snyder MP. Integrative omics for health and disease. Nat Rev Genet. 2018;19(5):299-310. doi: 10.1038/nrg.2018.4

 

  1. Lan L, Feng K, Wu Y, et al. Phenomic imaging. Phenomics. 2024;3(6):1-16. doi: 10.1007/s43657-023-00128-8

 

Next article in this issue
Share
Back to top
Journal of Clinical and Basic Psychosomatics, Electronic ISSN: 2972-4414 Print ISSN: 3060-8562, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept