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. 2025 Jul 23:9:25424823251362469.
doi: 10.1177/25424823251362469. eCollection 2025 Jan-Dec.

Causal associations and shared genetic etiology between neurodegenerative diseases and constipation

Weidong Sun  1 , Anlong Zhu  1 , Hanman Chang  2 , Junyi Xia  3 , Jun Gao  1 , Zhiqiang Zhang  4 , Fengxu Chi  1 , Yuekun Zhu  1 , Xuhui Bao  2   5
Affiliations

Causal associations and shared genetic etiology between neurodegenerative diseases and constipation

Weidong Sun et al. J Alzheimers Dis Rep. .

Abstract

Background: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.

Objective: We aim to investigate the causal link and shared genetic basis between NDDs and constipation.

Methods: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes.

Results: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades.

Conclusions: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.

Keywords: Alzheimer's disease; Mendelian; causal associations; constipation.

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Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
An overview of the study design.
Figure 2.
Figure 2.
Mr estimates for the neurodegenerative diseases on the risk of constipation in the primary MR analysis.
Figure 3.
Figure 3.
Scatter plots of MR analyses for the causal association between neurodegenerative diseases and the risk of constipation.
Figure 4.
Figure 4.
Meta-analysis of IVW results from primary and replication MR analysis for the causal association between neurodegenerative diseases and the risk of constipation.
Figure 5.
Figure 5.
Conditional quantile-quantile plot. The dashed line represents the expected distribution under the null hypothesis, while the leftward deflection indicated the extent of pleiotropic enrichment.
Figure 6.
Figure 6.
Shared loci between AD and constipation. The Manhattan plot illustrated the relationship between each SNP's -log10 transformed p-value (y-axis) and its chromosomal position (x-axis). The red horizontal line represents the statistical threshold for significant shared associations.
Figure 7.
Figure 7.
Go and KEGG functional enrichment analysis of mapped genes between AD and constipation.
See this image and copyright information in PMC

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