胃食管反流病与哮喘之间的遗传重叠和因果关系分析
2025/10/11
摘要
背景：胃食管反流病（GERD）和哮喘是常见的共病，有共同的遗传因素。然而，具体的位点和共同遗传结构的影响尚不明确。
方法：本研究获得GERD（71522例患者，261079名对照者）和哮喘（56167例患者，352255名对照者）的全基因组关联研究（GWAS）汇总统计数据。本研究通过连锁不平衡评分回归（LDSC）评估了GERD和哮喘之间的遗传相关性，通过双向孟德尔随机化（MR）探索潜在因果关系，并通过交叉性状GWAS荟萃分析和共定位分析确定共同风险位点。此外，本研究还通过基于汇总数据的孟德尔随机化（SMR）和转录组广泛关联研究（TWAS），确定了常见的功能基因。最后，本研究采用食管单细胞RNA测序（scRNA-seq）数据分析了健康个体和GERD患者的基因表达谱。
结果：本研究发现GERD与哮喘之间存在显著的遗传相关性（rg=0.37，P=0.19×10⁻³⁸），GERD对哮喘具有显著的因果关系（OR=1.22，P=0.54×10⁻⁵）。交叉性状荟萃分析显示，GERD和哮喘之间有56个共同的风险位点，其中包括51个新发现的位点。三个位点（rs61937247、rs7960225和rs769670）显示出共定位的证据。基因水平分析确定了GERD和哮喘之间的三个新的共享基因（RBM6、SUOX和MPHOSPH9）。单细胞RNA测序分析发现，这些基因在诊断为GERD的患者的免疫细胞中表达上调。
结论：本研究发现了GERD和哮喘之间新的共享遗传位点和候选基因，为上述疾病的共病遗传易感性和潜在机制提供了更深入的见解。
Unveiling the genetic overlap and causal links between gastroesophageal reflux disease and asthma.
Zhang Y, Li Y, Huang W, Tong S, Zeng R, Lyu Y, Leung FW, Chen K, Sha W, Chen H.
Abstract
BACKGROUND:Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined.
METHODS:We obtained genome-wide association study (GWAS) summary statistics for GERD (71,522 cases, 261,079 controls) and asthma (56,167 cases, 352,255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based mendelian randomization (SMR) and transcriptome-wide association study (TWAS) were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data.
RESULTS:We identified a significant genetic correlation between GERD and asthma (rg = 0.37, P = 6.19 × 10–38) and a significant causal effect of GERD on asthma (OR = 1.22, P = 1.54 × 10−5). Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes(RBM6, SUOX, and MPHOSPH9) between GERD and asthma. Single-cell RNA sequencing analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD.
CONCLUSION:Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases.
背景：胃食管反流病（GERD）和哮喘是常见的共病，有共同的遗传因素。然而，具体的位点和共同遗传结构的影响尚不明确。
方法：本研究获得GERD（71522例患者，261079名对照者）和哮喘（56167例患者，352255名对照者）的全基因组关联研究（GWAS）汇总统计数据。本研究通过连锁不平衡评分回归（LDSC）评估了GERD和哮喘之间的遗传相关性，通过双向孟德尔随机化（MR）探索潜在因果关系，并通过交叉性状GWAS荟萃分析和共定位分析确定共同风险位点。此外，本研究还通过基于汇总数据的孟德尔随机化（SMR）和转录组广泛关联研究（TWAS），确定了常见的功能基因。最后，本研究采用食管单细胞RNA测序（scRNA-seq）数据分析了健康个体和GERD患者的基因表达谱。
结果：本研究发现GERD与哮喘之间存在显著的遗传相关性（rg=0.37，P=0.19×10⁻³⁸），GERD对哮喘具有显著的因果关系（OR=1.22，P=0.54×10⁻⁵）。交叉性状荟萃分析显示，GERD和哮喘之间有56个共同的风险位点，其中包括51个新发现的位点。三个位点（rs61937247、rs7960225和rs769670）显示出共定位的证据。基因水平分析确定了GERD和哮喘之间的三个新的共享基因（RBM6、SUOX和MPHOSPH9）。单细胞RNA测序分析发现，这些基因在诊断为GERD的患者的免疫细胞中表达上调。
结论：本研究发现了GERD和哮喘之间新的共享遗传位点和候选基因，为上述疾病的共病遗传易感性和潜在机制提供了更深入的见解。
（中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校）
（Int J Surg. 2025 Sep 11. doi: 10.1097/JS9.0000000000003283. Epub ahead of print.）
Unveiling the genetic overlap and causal links between gastroesophageal reflux disease and asthma.
Zhang Y, Li Y, Huang W, Tong S, Zeng R, Lyu Y, Leung FW, Chen K, Sha W, Chen H.
Abstract
BACKGROUND:Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined.
METHODS:We obtained genome-wide association study (GWAS) summary statistics for GERD (71,522 cases, 261,079 controls) and asthma (56,167 cases, 352,255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based mendelian randomization (SMR) and transcriptome-wide association study (TWAS) were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data.
RESULTS:We identified a significant genetic correlation between GERD and asthma (rg = 0.37, P = 6.19 × 10–38) and a significant causal effect of GERD on asthma (OR = 1.22, P = 1.54 × 10−5). Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes(RBM6, SUOX, and MPHOSPH9) between GERD and asthma. Single-cell RNA sequencing analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD.
CONCLUSION:Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases.
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