Genome-wide association studies (GWAS) have identified several susceptibility loci for gastric cancer (GC), but the majority of identified single-nucleotide polymorphisms (SNPs) fall within the non-coding region and are likely to exert their biological function by modulating gene expression. To systematically estimate expression-associated SNPs (eSNPs) that confer genetic predisposition to GC, we evaluated the associations of 314,203 stomach tissue-specific eSNPs with GC risk in three GWAS datasets (2,631 cases and 4,373 controls). Subsequently, we conducted a gene-based analysis to calculate the cumulative effect of eSNPs through sequence kernel association combined test and Sherlock integrative analysis. At the SNP-level, we identified two novel variants (rs836545 at 7p22.1 and rs1892252 at 6p22.2) associated with GC risk. The risk allele carriers of rs836545-T and rs1892252-G exhibited higher expression levels of DAGLB (P = 3.70 × 10^–18) and BTN3A2 (P = 3.20 × 10^–5), respectively. Gene-based analyses identified DAGLB and FBXO43 as novel susceptibility genes for GC. DAGLB and FBXO43 were significantly overexpressed in GC tissues than in their adjacent tissues (P = 5.59 × 10^–7 and P = 3.90 × 10^–6, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients (P = 1.30 × 10^–7 and P = 7.60 × 10^–3, respectively). Co-expression genes with these two novel genes in normal stomach tissues were significantly enriched in several cancer-related pathways, including P53, MAPK and TGF-beta pathways. In summary, our findings confirm the importance of eSNPs in dissecting the genetic basis of GC, and the identified eSNPs and relevant genes will provide new insight into the genetic and biological basis for the mechanism of GC development.

全基因组关联研究（GWAS）已经确定了胃癌（GC）的几个易感基因座，但是大多数鉴定出的单核苷酸多态性（SNP）属于非编码区，并且可能通过调节基因发挥其生物学功能表达。为了系统地评估赋予遗传易感性的表达相关SNP（eSNPs），GC，我们评估了三个GWAS数据集（2,631例和4,373例对照）中314,203胃组织特异性eSNP与GC风险的关联。随后，我们进行了基于基因的分析，通过序列核结合试验和Sherlock整合分析来计算eSNP的累积效应。在SNP级别，我们确定了两个与GC风险相关的新变体（7p22.1处的rs836545和6p22.2处的rs1892252）。达格 （P= 3.70×10 ^–18）和BTN3A2 （P= 3.20×10 ^–5）。确定基于基因的分析达格 和 FBXO43 作为GC的新型易感基因。 达格 和 FBXO43 在GC组织中明显高于在其相邻组织中（P= 5.59×10 ^–7和P分别为3.90×10 ^–6），并且这两个基因的高表达水平与GC患者的预后不良相关（P= 1.30×10 ^–7和P分别为7.60×10 ^–3）。在正常胃组织中与这两个新基因的共表达基因在包括P53，MAPK和TGF-β在内的几种癌症相关途径中显着富集。总而言之，我们的发现证实了eSNPs在解剖GC遗传基础中的重要性，而鉴定出的eSNPs和相关基因将为GC发育机理的遗传和生物学基础提供新的见解。