Wang Chengyi, Lv Guoqing, Chen Erbao, Xue Yangyang, Zhou Bowen, Yang Miaomiao, Zhong Yanhuan
Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China.
Southern University of Science and Technology, Shenzhen, 518055, China.
Dig Dis Sci. 2025 May 30. doi: 10.1007/s10620-025-09083-y.
The aim of this study was to explore the shared genetic architecture between inflammatory bowel disease and depression and other upper gastrointestinal dysfunctions and inflammatory diseases, and to identify shared risk loci, potential key tissues, and associated genetic mechanisms to study.
Based on pooled data from a large-scale genome-wide association study (GWAS), we observed a genetic correlation between inflammatory bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and performed cross-trait pleiotropy analyses to detect shared pleiotropic loci and genes. In addition, we performed a series of functional annotation and tissue-specific analyses to determine the impact of pleiotropic genes. Genetic power enrichment analysis was used to detect key immune cells and tissues. Finally, immunological associations between these diseases were explored using an immunolocalization approach.
Our study highlights the existence of shared genetic mechanisms between depression, IBS, GORD, chronic gastritis, and IBD. A total of 160 promising pleiotropic loci were identified at the genome-wide significance level (P: 5 × 10) and annotation identified 54 dominant risk SNP loci, 30 of which passed causal co-localization tests. Further gene level analyses identified 2 unique pleiotropic genes such as rs142762983 and rs7865719. Pathway analyses identified nikolsky breast cancer 17q11 q21 amplicon, kegg type idiabetes mellitus, and gg intestinal immune network for iga production. The key role of these signaling pathways in these disorders was demonstrated by SNP level and gene level tissue enrichment analyses, which showed that pleiotropic mechanisms were significantly enriched in WholB blood, Spleen, Colon Transverse, and Small Intestine Terminal Ileum. Final analysis of immune cells by phenotypic level immunolocalization results showed 49 pleiotropic loci that support an important role for five unique immune cells in IBD and depression and three other gastrointestinal disorders through shared causal variants.
Our study demonstrates the existence of a genetic association between symptomatic bowel disease and depression and other upper gastrointestinal tract dysfunctions and inflammatory disorders and reveals underlying immunomodulatory mechanisms.
本研究旨在探索炎症性肠病与抑郁症以及其他上消化道功能障碍和炎症性疾病之间的共同遗传结构，识别共同的风险位点、潜在的关键组织以及相关的遗传机制以供研究。
基于大规模全基因组关联研究（GWAS）的汇总数据，我们观察了炎症性肠病与抑郁症以及其他上消化道功能障碍和炎症性疾病之间的遗传相关性，并进行了跨性状多效性分析以检测共同的多效性位点和基因。此外，我们进行了一系列功能注释和组织特异性分析以确定多效性基因的影响。使用遗传力富集分析来检测关键免疫细胞和组织。最后，采用免疫定位方法探索这些疾病之间的免疫关联。
我们的研究突出了抑郁症、肠易激综合征、胃食管反流病、慢性胃炎和炎症性肠病之间存在共同的遗传机制。在全基因组显著性水平（P：5×10）上共鉴定出160个有前景的多效性位点，注释确定了54个主要风险单核苷酸多态性位点，其中30个通过了因果共定位测试。进一步的基因水平分析鉴定出2个独特的多效性基因，如rs142762983和rs7865719。通路分析确定了17q11 q21扩增子的尼古拉斯基乳腺癌、2型糖尿病的KEGG通路以及肠道免疫网络中IgA产生相关通路。单核苷酸多态性水平和基因水平的组织富集分析证明了这些信号通路在这些疾病中的关键作用，表明多效性机制在全血、脾脏、横结肠和回肠末端显著富集。通过表型水平免疫定位结果对免疫细胞的最终分析显示，49个多效性位点通过共享的因果变异支持五种独特免疫细胞在炎症性肠病、抑郁症和其他三种胃肠道疾病中发挥重要作用。
我们的研究证明了症状性肠道疾病与抑郁症以及其他上消化道功能障碍和炎症性疾病之间存在遗传关联，并揭示了潜在的免疫调节机制。
