{
  "abstract": "Objective 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.Methods 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.Results Our study highlighted novel susceptibility loci near candidate genes (ie, UGT1A4, FADS1/3) 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.Conclusions 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, China"
      ],
      "name": "Haotian Chen"
    },
    {
      "affiliations": [
        "Zhenjiang First People’s Hospital, Zhenjiang, Jiangsu, China"
      ],
      "name": "Zhengye Liu"
    },
    {
      "affiliations": [
        "Peking Union Medical College Hospital, Beijing, China"
      ],
      "name": "Hanze Du"
    },
    {
      "affiliations": [
        "Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China"
      ],
      "name": "Mixue Zheng"
    },
    {
      "affiliations": [
        "Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China"
      ],
      "name": "Ziqi Wan"
    },
    {
      "affiliations": [
        "Peking Union Medical College Hospital, Beijing, China"
      ],
      "name": "Nan Zhao"
    },
    {
      "affiliations": [
        "Tsinghua University, Beijing, China"
      ],
      "name": "Guanqiao Li"
    },
    {
      "affiliations": [
        "Gastroenterology, Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China"
      ],
      "name": "Xiaoyin Bai"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, People’s Hospital of Xizang Autonomous Region, Lhasa, Xizang Autonomous Region, China",
        "Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China"
      ],
      "name": "Dong Wu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang Province, China"
      ],
      "name": "Jiarui Mi"
    }
  ],
  "title": "Integrative genome-wide analysis unveils the genetic landscape of gallstone disease and highlights novel loci with therapeutic potential",
  "uid": "a267330e-8b62-5f12-a154-c314cfbc564c"
}