Integrative analysis of gastric tissue transcriptomes and gastric cancer GWAS implicates candidate susceptibility genes.

Authors

Beiping Hu, Min Zhang, Yuhui Yu, Yongchao Liu, Jiawei Wang, Aiping Zhang, Qian Li, Yun Gao, Zhe Li, Lijun Bian, Yuanliang Gu, Xia Zhu, Qiang She, Xuefeng Gao, Bin Deng, Haisheng Fang, Caihong Hu, Yuheng Chen, Yan Chen, Xinya Wang, Xianyong Yin, Meng Zhu, Lu Wang, Yue Jiang, Jiaping Chen, Juncheng Dai, Hongxia Ma, Yanbing Ding, Caiwang Yan, Guangfu Jin

Published in

American journal of human genetics. Volume 113. Issue 7. Pages 1521-1542. Jul 02, 2026.

Abstract

Genome-wide association studies (GWASs) have identified at least 17 genetic variants associated with gastric cancer risk. However, the underlying genetic regulatory mechanisms remain poorly understood. We systematically performed genome-wide analyses of expression quantitative trait loci (eQTLs), splicing QTLs (sQTLs), and alternative polyadenylation QTLs (apaQTLs) using gastric biopsy tissues from 262 Chinese individuals, and we integrated these data with GWAS results from 10,254 gastric cancer cases and 10,914 controls. We identified 4,636 eGenes, 1,422 sGenes, and 511 apaGenes, with 55.3% of sGenes and 49.5% of apaGenes being distinct from eGenes. Notably, over half of the variants associated with shared genes were unique to a specific QTL type, with these variants characterized by a wide physical separation (median distance = 25.01 kb) and weak linkage disequilibrium (median r² = 0.42). Gastric cancer risk variants showed significant enrichment across all three QTL categories. Integrative transcriptome-wide association studies (TWASs) across expression, splicing, and alternative polyadenylation identified 34 genes at false discovery rate (FDR) <0.05; PSCA was implicated across all three regulatory layers. The candidates DIP2B and RMC1 were experimentally validated to promote gastric tumorigenesis both in vitro and in vivo. Functional analyses revealed that the rs11264361-T allele reduced FDPS exon 9 skipping, leading to increased expression of the full-length transcript, while the apaVariant rs7445 regulated UBE2L3 polyadenylation via ATXN2 binding, contributing to gastric cancer risk. Collectively, these results provide a comprehensive QTL resource in gastric tissues and demonstrate distinct regulatory mechanisms of eQTLs, sQTLs, and apaQTLs in gastric cancer development.

PMID:
42392035
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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