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Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer

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 syst...

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Autores principales: Ni, Jing, Deng, Bin, Zhu, Meng, Wang, Yuzhuo, Yan, Caiwang, Wang, Tianpei, Liu, Yaqian, Li, Gang, Ding, Yanbing, Jin, Guangfu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366424/
https://www.ncbi.nlm.nih.gov/pubmed/32754194
http://dx.doi.org/10.3389/fgene.2020.00679
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author Ni, Jing
Deng, Bin
Zhu, Meng
Wang, Yuzhuo
Yan, Caiwang
Wang, Tianpei
Liu, Yaqian
Li, Gang
Ding, Yanbing
Jin, Guangfu
author_facet Ni, Jing
Deng, Bin
Zhu, Meng
Wang, Yuzhuo
Yan, Caiwang
Wang, Tianpei
Liu, Yaqian
Li, Gang
Ding, Yanbing
Jin, Guangfu
author_sort Ni, Jing
collection PubMed
description 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.
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spelling pubmed-73664242020-08-03 Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer Ni, Jing Deng, Bin Zhu, Meng Wang, Yuzhuo Yan, Caiwang Wang, Tianpei Liu, Yaqian Li, Gang Ding, Yanbing Jin, Guangfu Front Genet Genetics 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. Frontiers Media S.A. 2020-07-10 /pmc/articles/PMC7366424/ /pubmed/32754194 http://dx.doi.org/10.3389/fgene.2020.00679 Text en Copyright © 2020 Ni, Deng, Zhu, Wang, Yan, Wang, Liu, Li, Ding and Jin. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Ni, Jing
Deng, Bin
Zhu, Meng
Wang, Yuzhuo
Yan, Caiwang
Wang, Tianpei
Liu, Yaqian
Li, Gang
Ding, Yanbing
Jin, Guangfu
Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title_full Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title_fullStr Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title_full_unstemmed Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title_short Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer
title_sort integration of gwas and eqtl analysis to identify risk loci and susceptibility genes for gastric cancer
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366424/
https://www.ncbi.nlm.nih.gov/pubmed/32754194
http://dx.doi.org/10.3389/fgene.2020.00679
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