Health Management Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
J Hum Genet. 2023 Sep;68(9):599-606. doi: 10.1038/s10038-023-01151-3. Epub 2023 May 18.
In recent decades, upper gastrointestinal (GI) diseases have been highly prevalent worldwide. Although genome-wide association studies (GWASs) have identified thousands of susceptibility loci, only a few of them were conducted for chronic upper GI disorders, and most of them were underpowered and with small sample sizes. Additionally, for the known loci, only a tiny fraction of heritability can be explained and the underlying mechanisms and related genes remain unclear. In this study, we conducted a multi-trait analysis by the MTAG software and a two-stage transcriptome-wide association study (TWAS) with UTMOST and FUSION for seven upper GI diseases (oesophagitis, gastro-oesophageal reflux disease, other diseases of oesophagus, gastric ulcer, duodenal ulcer, gastritis and duodenitis and other diseases of stomach and duodenum) based on summary GWAS statistics from UK Biobank. In the MTAG analysis, we identified 7 loci associated with these upper GI diseases, including 3 novel ones at 4p12 (rs10029980), 12q13.13 (rs4759317) and 18p11.32 (rs4797954). In the TWAS analysis, we revealed 5 susceptibility genes in known loci and identified 12 novel potential susceptibility genes, including HOXC9 at 12q13.13. Further functional annotations and colocalization analysis indicated that rs4759317 (A>G) driven the association for GWAS signals and expression quantitative trait loci (eQTL) simultaneously at 12q13.13. The identified variant acted by decreasing the expression of HOXC9 to affect the risk of gastro-oesophageal reflux disease. This study provided insights into the genetic nature of upper GI diseases.
近几十年来，全球范围内上消化道（GI）疾病的患病率一直很高。尽管全基因组关联研究（GWAS）已经确定了数千个易感性位点，但只有少数针对慢性上消化道疾病进行了研究，而且大多数研究的样本量较小，效力不足。此外，对于已知的位点，只有一小部分遗传率可以解释，其潜在机制和相关基因仍然不清楚。在这项研究中，我们使用 MTAG 软件进行了多性状分析，并使用 UTMOST 和 FUSION 进行了两阶段全转录组关联研究（TWAS），对 UK Biobank 汇总的 GWAS 统计数据进行了分析，共涉及七种上消化道疾病（食管炎、胃食管反流病、食管其他疾病、胃溃疡、十二指肠溃疡、胃炎和十二指肠炎及胃和十二指肠的其他疾病）。在 MTAG 分析中，我们确定了与这些上消化道疾病相关的 7 个位点，包括在 4p12（rs10029980）、12q13.13（rs4759317）和 18p11.32（rs4797954）的 3 个新位点。在 TWAS 分析中，我们在已知的位点中揭示了 5 个易感性基因，并确定了 12 个新的潜在易感性基因，包括 12q13.13 上的 HOXC9。进一步的功能注释和共定位分析表明，rs4759317（A>G）在 12q13.13 处同时驱动了与 GWAS 信号和表达数量性状基因座（eQTL）的关联。该鉴定出的变异通过降低 HOXC9 的表达来影响胃食管反流病的风险。这项研究为上消化道疾病的遗传性质提供了新的见解。
