Abstract
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.
Highlights
Gastric cancer (GC) is the fifth most common neoplasm and second leading cause of cancer-related death globally
After linkage disequilibrium (LD) pruning, we identified a total of 1,222 index expression-associated single-nucleotide polymorphism (SNP) (eSNPs) at P < 0.05
We discovered two independent novel eSNPs associated with gastric cancer (GC) risk, which together captured nearly 12.37% of the phenotypic variance explained by all identified genetic loci
Summary
Gastric cancer (GC) is the fifth most common neoplasm and second leading cause of cancer-related death globally. There were approximately one million newly diagnosed GC cases and 780,000 deaths in 2018 (Bray et al, 2018). Half of the new GC cases and deaths worldwide occur in China, indicating a major public health burden (Chen et al, 2016). We and other groups have reported a number of susceptibility loci for GC through genome-wide association study (GWAS), which only explain a fraction of GC heritability (Abnet et al, 2010; Shi et al, 2011; Wang et al, 2017; Park et al, 2019). The vast majority of disease-related variants discovered by GWAS fall within intergenic or non-coding regions, which may regulate the expression of target genes and influence the process of pathogenesis (Maurano et al, 2012)
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