Sun Weidong, Zhu Anlong, Chang Hanman, Xia Junyi, Gao Jun, Zhang Zhiqiang, Chi Fengxu, Zhu Yuekun, Bao Xuhui
Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Center for Clinical Research, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
J Alzheimers Dis Rep. 2025 Jul 23;9:25424823251362469. doi: 10.1177/25424823251362469. eCollection 2025 Jan-Dec.
There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated.
We aim to investigate the causal link and shared genetic basis between NDDs and constipation.
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.
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.
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.
越来越多的证据表明神经退行性疾病（NDDs）与便秘之间存在关联；然而，它们的遗传关系和因果机制仍未得到充分阐明。
我们旨在研究NDDs与便秘之间的因果联系和共同的遗传基础。
我们从大规模全基因组关联研究中获得了汇总统计数据，涵盖五种NDDs，包括阿尔茨海默病（AD）、帕金森病（PD）、多发性硬化症（MS）、肌萎缩侧索硬化症（ALS）、路易体痴呆（LBD）以及便秘。主要分析采用五种孟德尔随机化方法来评估因果效应，同时利用连锁不平衡评分回归（LDSC）和高分辨率似然性（HDL）来研究遗传相关性。此外，在复合零假设（PLACO）下使用多效性分析以及功能映射和注释（FUMA）来识别显著的多效性单核苷酸多态性（SNPs）。最后，进行富集分析以探索与已识别的多效性基因相关的生物学途径。
孟德尔随机化分析显示AD与便秘风险增加之间存在显著的因果关系（比值比[OR]=1.043，95%置信区间[CI]：1.015 - 1.073，p = 0.003），而在PD、MS、ALS、LBD与便秘风险之间未发现因果关系（p>0.05）。LDSC和HDL分析显示AD与便秘之间存在显著的正遗传相关性。使用PLACO结合FUMA，我们识别出30个重叠的多效性位点，通路富集分析揭示了与淀粉样β蛋白（Aβ）代谢和加工、tau蛋白过程以及补体和凝血级联反应相关的重要生物学途径。
我们的研究表明AD是便秘的一个促成因素，并揭示了连接AD和便秘的复杂遗传机制，这对这两种疾病的诊断和治疗具有重要意义。
