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Functional Annotation and Gene Set Analysis of Gastric Cancer Risk Loci in a Korean Population

최일주|김영일|성주헌|이정희|김정선|편효진|마다와
대한암학회 (Korean Cancer Association)|2024.01|Cancer Research and Treatment|제56권 제1호|pp. 191-198|DOI 10.4143/crt.2022.958

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키워드

Genome-wide association studyStomach neoplasmsPost-GWASFunctional annotationGene enrichment analysis
주제분류의학일반

초록

Purpose 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.Materials and 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 <i>KLHDC4</i> gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10<sup>–83</sup>). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10<sup>–6</sup> (0.05/13,114); <i>DEFB108B</i> had the lowest p=5.94×10<sup>–15</sup>, followed by <i>FAM86C1</i> (p=1.74×10<sup>–14</sup>), <i>PSCA</i> (p=1.81×10<sup>–14</sup>), and <i>KLHDC4</i> (p=5.00×10<sup>–10</sup>). In gene prioritizing, <i>KLDHC4</i> was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, <i>FOLR2, PSCA, LY6K, LYPD2</i>, and <i>LY6E</i> showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway.Conclusion 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.

Abstract

Purpose 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. Materials and 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. Conclusion 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.

참고문헌 (39)

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