Presentation Information
[OE7-1]East Asian-specific and cross-ancestry genome-wide meta-analyses provide new insights into peptic ulcer disease genetics
○Yunye He1, Masaru Koido1, Yoichi Sutoh2, Mingyang Shi1, Yayoi Yamasaki2, Takayuki Morisaki3, Akiko Nagai3, Yoshinori Murakami3, Chizu Tanikawa1, Tsuyoshi Hachiya2, Koichi Matsuda1,3, Atsushi Shimizu2, Yoichiro Kamatani1 (1.Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan, 2.Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan, 3.Institute of Medical Science, The University of Tokyo, Tokyo, Japan)
Peptic ulcer disease (PUD) is the acid-induced injury of the digestive tract, mainly occurring in the stomach (Gastric ulcer; GU) or duodenum (Duodenal ulcer; DU). Despite several risk loci for PUD identified in previous genome-wide association studies (GWAS), the underlying genetics largely remain unclear. We conducted a large-scale cross-ancestry meta-analysis for PUD GWAS with four Japanese and two European studies (52,032 cases and 905,344 controls), discovering 29 novel independent loci that were highly concordant across ancestries. GU shared the same risk loci with DU but showed smaller genetic effect sizes than DU, indicating higher heterogeneity of GU. Downstream analyses highlighted plausible biologies, such as blood coagulation by integrating expression and protein quantitative trait locus analyses. Moreover, the gene-level analysis showed that genetic factors are enriched in highly expressed genes in stomach tissue, especially in somatostatin-producing D cells from stomach and duodenum single-cell RNA sequencing datasets. We found that EFNA1, PTGER4, and PSCA showed strong but opposite effects on DU and gastric cancers (GC), suggesting the potential mechanisms contributing to the decreased risk of GC in DU patients. H.pylori (HP)-stratified analysis found HP-related host genetic locus at CCKBR, marking its role in HP-mediated PUD etiology. In summary, we revealed potential genes and biological mechanisms involved in genetic susceptibility to PUD and its subtypes, and their genetic similarities as well as differences from GC.