Huanxin Ding, Chuxuan Liu, Qing Sun, Yue Jiang, Qian Xu, Zhenguo Zhu, Xin Jin, Qibo Huang, Yue Li, Yingchao Song, Zenglin Liu, Tianming Yu, B. A. Shi, Delin Tan, Linzehao Li, Frank Mentch, Joseph Glessner, Xiao Chang, Hakon Hakonarson, Guangyong Zhang
Gastric cancer is a leading cause of cancer-related death, particularly in East Asia, yet its genetic basis remains incompletely understood. Using genome-wide association study data from BioBank Japan, we show that gastric cancer shares significant genetic associations with 25 other phenotypes, most notably cardiovascular conditions such as angina pectoris and myocardial infarction. Mendelian randomization supports a causal role of these traits in gastric cancer risk. Multitrait analysis of GWAS reveals a novel pleiotropic locus at 12q22 (rs12814712) that is shared between gastric cancer and cardiovascular traits. Functional experiments demonstrate that the risk allele at this locus reduces transcriptional activity and downregulates the expression of nearby genes, particularly VEZT. In gastric cancer cells, overexpression of VEZT and NR2C1 suppress proliferation and migration, whereas their knockdown promotes malignancy. Our analysis identifies rs12814712 as a novel susceptibility locus for gastric cancer and underscores its regulatory role in disease-related gene networks. Multi-trait genetic analysis in East Asians identifies a novel gastric cancer risk locus shared with cardiovascular traits and shows that this variant modulates regulation of nearby genes, including VEZT, with functional effects on gastric cancer cell behaviour.