Chen Haotian, Liu Zhengye, Du Hanze, Zheng Mixue, Wan Ziqi, Zhao Nan, Li Guanqiao, Bai Xiaoyin, Wu Dong, Mi Jiarui
Department of Gastroenterology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, China.
Zhenjiang First People's Hospital, Zhenjiang, Jiangsu, China.
BMJ Open Gastroenterol. 2025 Sep 14;12(1):e001976. doi: 10.1136/bmjgast-2025-001976.
Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to identify novel genetic loci associated with GD, explore their clinical implications and investigate their therapeutic potential.
We conducted a genome-wide association study from the UK Biobank followed by a meta-analysis, integrating summary statistics from the FinnGen R11, with further replication from Biobank Japan. Using systematic bioinformatic approaches, we performed gene prioritisation, colocalisation analysis, transcriptome-wide association study, Mendelian randomisations, cross-trait genetic correlations, phenome-wide association study, clinical investigations and gene-environment interactions by leveraging data from the FinnGen, Genotype-Tissue Expression project and Liver Cell Atlas single-cell transcriptomics data set.
Our study highlighted novel susceptibility loci near candidate genes (ie, , ) associated with GD, expanding the known genetic landscape. Functional annotation and colocalisation analysis implicated that the independent variants are involved in various hepatocyte functions, including bile secretion, cellular glucuronidation and cholesterol gallstone pathway. Mendelian randomisation established causal relationships between the level of unsaturated fatty acids and GD risk. We also demonstrated the implications of indirect bilirubin level in GD risk stratification and the protective effect of oily fish intake in genetically susceptible individuals.
This study provides new insights into the genetic basis of GD and highlights the role of hepatocytes in GD pathogenesis. These findings have implications for the personalised prevention strategies and new therapeutic interventions in individuals predisposed to GD.
胆结石病（GD）是一种常见的胃肠道疾病，具有重要的遗传因素。尽管已知有风险因素，但GD的遗传基础仍未完全了解。我们旨在识别与GD相关的新遗传位点，探索其临床意义并研究其治疗潜力。
我们对英国生物银行进行了全基因组关联研究，随后进行了荟萃分析，整合了来自芬兰基因库R11的汇总统计数据，并在日本生物银行进行了进一步验证。我们采用系统的生物信息学方法，通过利用来自芬兰基因库、基因型-组织表达项目和肝细胞图谱单细胞转录组数据集的数据，进行基因优先级排序、共定位分析、全转录组关联研究、孟德尔随机化、跨性状遗传相关性分析、全表型关联研究、临床研究以及基因-环境相互作用分析。
我们的研究突出了与GD相关的候选基因（即 ， ）附近的新易感位点，扩展了已知的遗传图谱。功能注释和共定位分析表明，独立变异参与了各种肝细胞功能，包括胆汁分泌、细胞葡萄糖醛酸化和胆固醇胆结石途径。孟德尔随机化确定了不饱和脂肪酸水平与GD风险之间的因果关系。我们还证明了间接胆红素水平在GD风险分层中的意义以及油性鱼类摄入对遗传易感个体的保护作用。
本研究为GD的遗传基础提供了新的见解，并突出了肝细胞在GD发病机制中的作用。这些发现对GD易感个体的个性化预防策略和新的治疗干预具有重要意义。
