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

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

Acknowledgments

None.

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.

Author contributions

Conceptualization: Cong Zhou, Hao Yu, Chuanxin Liu, Shuai Wang

Data curation: Sen Li, Shanling Ji, Shengbo Han, Zhengyang Chang, Mingfeng Fan, Yongming Huang

Formal analysis: Ruiqing Wang

Funding acquisition: Hao Yu, Shuai Wang

Investigation: Cong Zhou

Methodology: Sen Li, Shanling Ji, Ruiqing Wang, Shengbo Han, Zhengyang Chang, Mingfeng Fan, Yongming Huang

Project administration: Shuai Wang

Resources: Cong Zhou, Hao Yu, Chuanxin Liu

Software: Sen Li, Shanling Ji, Shengbo Han, Zhengyang Chang

Supervision: Hao Yu, Chuanxin Liu, Shuai Wang

Validation: Cong Zhou, Ruiqing Wang, Hao Yu, Chuanxin Liu, Shuai Wang

Visualization: Ruiqing Wang, Sen Li, Shanling Ji, Shengbo Han, Zhengyang Chang, Mingfeng Fan, Yongming Huang

Writing - original draft: Cong Zhou, Ruiqing Wang

Writing - review & editing: Cong Zhou, Sen Li, Shanling Ji, Shengbo Han, Zhengyang Chang, Hao Yu, Chuanxin Liu, Mingfeng Fan, Yongming Huang, Shuai Wang

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

All data are publicly available. The data sources for this study include the FinnGen consortium (https://r10. finngen.fi/) and BIG-S2 (https://www.med.unc.edu/bigs2/data/gwas-summary-statistics/).

Further disclosure

Part of the findings have been presented at the 30th Annual Conference of the Psychosomatic Medicine Branch of the Chinese Medical Association in Fuzhou, China.

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