Cancer Res Treat.  2024 Jan;56(1):191-198. 10.4143/crt.2022.958.

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

• Pyun H
• Gunathilake M
• Lee J
• Choi IJ
• Kim YI
• Sung J
• Kim J

• KMID: 2550335
• DOI: http://doi.org/10.4143/crt.2022.958

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.

Keyword

Genome-wide association study; Post-GWAS; Functional annotation; Gene enrichment analysis; Stomach neoplasms

Figure

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  Fig. 1 Overall workflow. Starting from gastric cancer genome-wide association study (GWAS) with total 6,080 samples, functional annotation of identified single nucleotide polymorphisms (SNPs) across 6 genomic risk loci, 71 genes prioritized by positional, expression quantitative trait loci (eQTL), and chromatin interaction gene mapping approaches, and gene-based analysis with all genes and prioritized genes for further biological pathway understanding. KoGES, Korean Genome Epidemiology Study; NCC, National Cancer Center.

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  Fig. 2 Manhattan plot. The Manhattan plot of gastric cancer genome-wide association study (GWAS) result is shown. (A) Single nucleotide polymorphism (SNP)–based GWAS result. rs2303771 in chromosome 16 had the most significant signal. SNPs with most significant p-value in genomic loci were annotated with their rsID. (B) Gene-based GWAS result. 11,314 mapped coding genes based on all SNPs in the data were used for GWAS.

Reference

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