■我们旨在通过GWAS鉴定与胃癌(GC)风险相关的SNP,并探索具有表达模式的相关基因和基因集的途径富集。
■研究人群由来自国家癌症中心和韩国基因组流行病学研究的城市社区的1,253例GC病例和4,827例对照组成,并进行了基因分型。SNP被注释,并通过FUMA的三种作图方法映射到基因以进行优先级排序。使用MAGMA对完整的GWAS汇总数据进行基于基因的分析和基因集分析。用那些优先排序的基因进行基因集途径富集测试。
■在GWAS中,rs2303771,KLHDC4基因的非同义变体是与GC显着相关的最高SNP(OR=2.59,p=1.32x0-83)。在GWAS后,71个基因被优先考虑。在基于基因的GWAS中,7个基因在显著p<3.80×10-6(0.05/13114)下;DEFB108B的p=5.94×10-15最低,其次是FAM86C1(p=1.74×10-14),PSCA(p=1.81x10-14),和KLHDC4(p=5.00×10-10)。在基因优先排序中,KLDHC4是唯一用所有三种基因作图方法作图的基因。在优先基因的途径富集试验中,FOLR2,PSCA,LY6K,LYPD2和LY6E显示出与膜的细胞成分相关的强烈富集;通过合成糖基磷脂酰肌醇(GPI)锚定蛋白途径进行的翻译后修饰。
■虽然37个SNP与GC的风险显著相关,与嘌呤代谢相关的信号通路相关的基因和细胞膜上的GPI锚定蛋白被确定为在GC中起重要作用。
OBJECTIVE: We aimed to identify the associated single nucleotide polymorphisms (SNPs) with gastric cancer (GC) risk by genome-wide association study (GWAS) and to explore the pathway enrichment of implicated genes and gene-sets with expression patterns.
METHODS: The study population was comprised of 1,253 GC cases and 4,827 controls from National Cancer Center and an urban community of the Korean Genome Epidemiology Study and their genotyping was performed. SNPs were annotated, and mapped to genes to prioritize by three mapping approaches by functional mapping and annotation (FUMA). The gene-based analysis and gene-set analysis were conducted with full GWAS summary data using MAGMA. Gene-set pathway enrichment test with those prioritized genes were performed.
RESULTS: In GWAS, rs2303771, a nonsynonymous variant of KLHDC4 gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10-83). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10-6 (0.05/13,114); DEFB108B had the lowest p=5.94×10-15, followed by FAM86C1 (p=1.74×10-14), PSCA (p=1.81×10-14), and KLHDC4 (p=5.00×10-10). In gene prioritizing, KLDHC4 was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, FOLR2, PSCA, LY6K, LYPD2, and LY6E showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway.
CONCLUSIONS: While 37 SNPs were significantly associated with the risk of GC, genes involved in signaling pathways related to purine metabolism and GPI-anchored protein in cell membrane are pinpointed to be playing important role in GC.