Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, Seoul, 03080, Korea.
Cancer Research Institute, Seoul National University, Seoul, Korea.
Gastric Cancer. 2023 Jul;26(4):517-527. doi: 10.1007/s10120-023-01380-7. Epub 2023 Mar 30.
A gene or variant has pleiotropic effects, and genetic variant identification across multiple phenotypes can provide a comprehensive understanding of biological pathways shared among different diseases or phenotypes. Discovery of genetic loci associated with multiple diseases can simultaneously support general interventions. Several meta-analyses have shown genetic associations with gastric cancer (GC); however, no study has identified associations with other phenotypes using this approach.
Here, we applied disease network analysis and gene-based analysis (GBA) to examine genetic variants linked to GC and simultaneously associated with other phenotypes. We conducted a single-nucleotide polymorphism (SNP) level meta-analysis and GBA through a systematic genome-wide association study (GWAS) linked to GC, to integrate published results for the SNP variants and group them into major GC-associated genes. We then performed disease network and expression quantitative trait loci (eQTL) analyses to evaluate cross-phenotype associations and expression levels of GC-related genes.
Seven genes (MTX1, GBAP1, MUC1, TRIM46, THBS3, PSCA, and ABO) were associated with GC as well as blood urea nitrogen (BUN), glomerular filtration rate (GFR), and uric acid (UA). In addition, 17 SNPs regulated the expression of genes located on 1q22, 24 SNPs regulated the expression of PSCA on 8q24.3, and rs7849820 regulated the expression of ABO on 9q34.2. Furthermore, rs1057941 and rs2294008 had the highest posterior causal probabilities of being a causal candidate SNP in 1q22, and 8q24.3, respectively.
These findings identified seven GC-associated genes exhibiting a cross-association with GFR, BUN, and UA.
一个基因或变异具有多种效应，跨多种表型鉴定遗传变异可以全面了解不同疾病或表型之间共享的生物途径。发现与多种疾病相关的遗传基因座可以同时支持一般干预措施。有几项荟萃分析表明胃癌（GC）与遗传有关；然而，没有研究使用这种方法发现与其他表型相关的关联。
在这里，我们应用疾病网络分析和基于基因的分析（GBA）来检查与 GC 相关且同时与其他表型相关的遗传变异。我们进行了单核苷酸多态性（SNP）水平的荟萃分析和 GBA 通过与 GC 相关的全基因组关联研究（GWAS），将已发表的 SNP 变体整合并将它们分为主要与 GC 相关的基因。然后，我们进行了疾病网络和表达数量性状基因座（eQTL）分析，以评估跨表型关联和 GC 相关基因的表达水平。
有七个基因（MTX1、GBAP1、MUC1、TRIM46、THBS3、PSCA 和 ABO）与 GC 以及血尿素氮（BUN）、肾小球滤过率（GFR）和尿酸（UA）相关。此外，17 个 SNP 调节位于 1q22 上的基因的表达，24 个 SNP 调节位于 8q24.3 上的 PSCA 的表达，rs7849820 调节位于 9q34.2 上的 ABO 的表达。此外，rs1057941 和 rs2294008 在 1q22 和 8q24.3 中分别是因果候选 SNP 的最高后验因果概率。
这些发现确定了七个与 GC 相关的基因，这些基因与 GFR、BUN 和 UA 具有交叉关联。
