Objective  To elucidate the mechanisms of susceptibility genes on chromosome 1q22 for gastric cancer (GC) development.

  Methods  Using the genotype-tissue expression database, the associations between independent effect loci and the expression levels of genes around the loci were analyzed. For the candidate susceptibility genes, differential gene expression (DGE) analysis was performed using population samples. The role of the susceptibility genes in the development of GC was explored through in vitro and in vivo experiments. The downstream pathways and mechanisms involved in the pathogenesis of GC were further explored through RNA sequencing.

  Results  Expression quantitative trait loci (eQTL) analysis confirmed that the rs760077 genotype was significantly correlated with the expression levels of THBS3, GBA, and GBAP1 (P-values were 1.20×10^-21, 1.80×10^-4, and 3.49×10^-17, respectively). DGE analysis and cell phenotype experiments confirmed that GBAP1 was highly expressed in GC tissues. The knockdown of GBAP1 significantly inhibited the proliferation of GC cells and reduced the growth of xenograft tumors in nude mice. RNA sequencing showed that GBAP1 could affect the expression levels of PHGDH, PSAT1, and PSPH and participate in various metabolic pathways, including those involved in glycine, serine, threonine, and carbon metabolism.

  Conclusions  This study confirmed that genetic variation in the 1q22 region could affect the expression of PHGDH, PSAT1, and PSPH, which code for key enzymes in amino acid synthesis, by regulating the expression of the pro-oncogene GBAP1, thereby promoting the occurrence of GC.