Zeng Ruijie, Wang Jinghua, Jiang Rui, Yang Jie, Zheng Chunwen, Wu Huihuan, Zhuo Zewei, Yang Qi, Li Jingwei, Leung Felix W, Sha Weihong, Chen Hao
Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
Aging Dis. 2023 Aug 1;14(4):1349-1359. doi: 10.14336/AD.2022.12209.
Published observational studies have revealed the connection between neurodegenerative disorders and inflammatory bowel disease (IBD), whereas the causal association remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between neurodegenerative disorders and IBD. Two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], Parkinson's disease [PD], and multiple sclerosis [MS]). Shared genetic loci, functional interpretation, and transcriptomic profiles were further investigated in ALS and IBD. We identified that genetic predisposition to IBD was suggestively associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD was not genetically associated with an increased risk of AD, PD, or MS (and vice versa). Two shared genetic loci (rs6571361 and rs7154847) were derived, and SCFD1, G2E3, and HEATR5A were further identified as novel risk genes with enriched functions related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with ALS or IBD. Our study reveals the suggestively protective role of IBD on ALS, and does not support the causality of AD, PD, or MS on IBD (and vice versa). Our findings indicate possible shared genetic architecture and pathways between ALS and IBD. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.
已发表的观察性研究揭示了神经退行性疾病与炎症性肠病（IBD）之间的联系，但其因果关系仍 largely 不清楚。我们的研究旨在评估因果关系，并确定神经退行性疾病和 IBD 之间共享的遗传结构。进行了两样本孟德尔随机化分析，以评估 IBD 与神经退行性疾病（肌萎缩侧索硬化症 [ALS]、阿尔茨海默病 [AD]、帕金森病 [PD] 和多发性硬化症 [MS]）之间的因果关系。在 ALS 和 IBD 中进一步研究了共享的基因座、功能解释和转录组谱。我们发现，IBD 的遗传易感性与 ALS 的较低发病几率存在提示性关联（优势比 [OR] 0.96，95% 置信区间 [CI] 0.94 至 0.99）。相比之下，IBD 在遗传上与 AD、PD 或 MS 的风险增加无关（反之亦然）。得出了两个共享的基因座（rs6571361 和 rs7154847），并进一步确定 SCFD1、G2E3 和 HEATR5A 为具有与膜运输相关功能富集的新风险基因。在 ALS 或 IBD 患者中，G2E3 存在差异表达且与 SCFD1 显著相关。我们的研究揭示了 IBD 对 ALS 可能具有的保护作用，并不支持 AD、PD 或 MS 对 IBD 的因果关系（反之亦然）。我们的研究结果表明 ALS 和 IBD 之间可能存在共享的遗传结构和途径。这些结果为 IBD 和神经退行性疾病的发病机制及治疗提供了见解。
