East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease

Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer; GU) or duodenum (duodenal ulcer; DU). We conducted a large-scale cross-ancestry meta-analysis of PUD combining genome-wide association studies with four Japanese and two European studies (52,032 cases and 905,344 controls), and discovered 25 novel loci highly concordant across ancestries. Based on these loci, an examination of similarities and differences in genetic architecture between GU and DU demonstrated that GU shared the same risk loci as DU, although with smaller genetic effect sizes and higher polygenicity than DU, indicating higher heterogeneity of GU. H. pylori (HP)-stratified analysis found an HP-related host genetic locus, marking its role in HP-mediated PUD etiology. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD to be enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We want to acknowledge all the participants and investigators of BioBank Japan, Tohoku Medical Megabank, UK Biobank, and FinnGen. We express our gratitude to Prof. Mark Lathrop for his valuable support. This research was supported by the Ministry of Education, Culture, Sports, Sciences and Technology (MEXT) of Japanese government and the Japan Agency for Medical Research and Development (AMED) under grant numbers JP21km0605001 (the BioBank Japan project), JP15km0105004 and JP21tm0124006 (the Tohoku Medical Megabank Project, Special Account for the Reconstruction of the Great East Japan Earthquake), JP20km0405001 (for the supercomputer resource), and JP21km0405215 (to C.T., K.M., and Y.K.). We thank the Human Genome Center, the Institute of Medical Science, the University of Tokyo for providing the super-computing resource used in this study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees at the Institute of Medical Science, the University of Tokyo (application number 29-74-A0215), and Iwate Tohoku Medical Megabank Organization, Iwate Medical University (application number HG H25-2) approved this research project. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics, including the results of GWAS at the discovery stage and that of the East Asian-specific and cross-ancestry meta-analysis in this study, will be available at National Bioscience Database Center (NBDC, ) Human Database or Japanese ENcyclopedia of GEnetic associations by Riken (JENGER, ) website upon its acceptance by a journal. Genotype data for BBJ were deposited at NBDC Human Database (BBJ1-180K, research ID:hum0014; BBJ1-12K and BBJ2-42K, research ID:hum0311).