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Abstract：
BACKGROUND: Observational studies have preliminarily revealed an association between smoking and gastroesophageal reflux disease (GERD). However, little is known about the causal relationship and shared genetic architecture between the two. This study aims to explore their common genetic correlations by leveraging genome-wide association studies (GWAS) of smoking behavior-specifically, smoking initiation (SI), never smoking (NS), ever smoking (ES), cigarettes smoked per day (CPD), age of smoking initiation(ASI) and GERD.
METHODS: Firstly, we conducted global cross-trait genetic correlation analysis and heritability estimation from summary statistics (HESS) to explore the genetic correlation between smoking behavior and GERD. Then, a joint cross-trait meta-analysis was performed to identify shared \"pleiotropic SNPs\" between smoking behavior and GERD, followed by co-localization analysis. Additionally, multi-marker analyses using annotation (MAGMA) were employed to explore the degree of enrichment of single nucleotide polymorphism (SNP) heritability in specific tissues, and summary data-based Mendelian randomization (SMR) was further utilized to investigate potential functional genes. Finally, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the smoking behavior and GERD.
RESULTS: Consistent genetic correlations were observed through global and local genetic correlation analyses, wherein SI, ES, and CPD showed significantly positive genetic correlations with GERD, while NS and ASI showed significantly negative correlations. HESS analysis also identified multiple significantly associated loci between them. Furthermore, three novel \"pleiotropic SNPs\" (rs4382592, rs200968, rs1510719) were identified through cross-trait meta-analysis and co-localization analysis to exist between SI, NS, ES, ASI, and GERD, mapping the genes MED27, HIST1H2BO, MAML3 as new pleiotropic genes between SI, NS, ES, ASI, and GERD. Moreover, both smoking behavior and GERD were found to be co-enriched in multiple brain tissues, with GMPPB, RNF123, and RBM6 identified as potential functional genes co-enriched in Cerebellar Hemisphere, Cerebellum, Cortex/Nucleus accumbens in SI and GERD, and SUOX identified in Caudate nucleus, Cerebellum, Cortex in NS and GERD. Lastly, consistent causal relationships were found through MR analysis, indicating that SI, ES, and CPD increase the risk of GERD, while NS and higher ASI decrease the risk.
CONCLUSIONS: We identified genetic loci associated with smoking behavior and GERD, as well as brain tissue sites of shared enrichment, prioritizing three new pleiotropic genes and four new functional genes. Finally, the causal relationship between smoking behavior and GERD was demonstrated, providing insights for early prevention strategies for GERD.
METHODS: Firstly, we conducted global cross-trait genetic correlation analysis and heritability estimation from summary statistics (HESS) to explore the genetic correlation between smoking behavior and GERD. Then, a joint cross-trait meta-analysis was performed to identify shared \"pleiotropic SNPs\" between smoking behavior and GERD, followed by co-localization analysis. Additionally, multi-marker analyses using annotation (MAGMA) were employed to explore the degree of enrichment of single nucleotide polymorphism (SNP) heritability in specific tissues, and summary data-based Mendelian randomization (SMR) was further utilized to investigate potential functional genes. Finally, Mendelian randomization (MR) analysis was conducted to explore the causal relationship between the smoking behavior and GERD.
RESULTS: Consistent genetic correlations were observed through global and local genetic correlation analyses, wherein SI, ES, and CPD showed significantly positive genetic correlations with GERD, while NS and ASI showed significantly negative correlations. HESS analysis also identified multiple significantly associated loci between them. Furthermore, three novel \"pleiotropic SNPs\" (rs4382592, rs200968, rs1510719) were identified through cross-trait meta-analysis and co-localization analysis to exist between SI, NS, ES, ASI, and GERD, mapping the genes MED27, HIST1H2BO, MAML3 as new pleiotropic genes between SI, NS, ES, ASI, and GERD. Moreover, both smoking behavior and GERD were found to be co-enriched in multiple brain tissues, with GMPPB, RNF123, and RBM6 identified as potential functional genes co-enriched in Cerebellar Hemisphere, Cerebellum, Cortex/Nucleus accumbens in SI and GERD, and SUOX identified in Caudate nucleus, Cerebellum, Cortex in NS and GERD. Lastly, consistent causal relationships were found through MR analysis, indicating that SI, ES, and CPD increase the risk of GERD, while NS and higher ASI decrease the risk.
CONCLUSIONS: We identified genetic loci associated with smoking behavior and GERD, as well as brain tissue sites of shared enrichment, prioritizing three new pleiotropic genes and four new functional genes. Finally, the causal relationship between smoking behavior and GERD was demonstrated, providing insights for early prevention strategies for GERD.
摘要：
背景：观察性研究初步揭示了吸烟与胃食管反流病（GERD）之间的关联。然而,对两者之间的因果关系和共有的遗传结构知之甚少。这项研究旨在通过利用吸烟行为的全基因组关联研究（GWAS）来探索它们共同的遗传相关性，吸烟开始（SI），从不吸烟（NS），曾经吸烟（ES），每天吸烟(CPD)，吸烟起始年龄（ASI）和GERD。
方法：首先，我们进行了全局交叉性状遗传相关分析和汇总统计(HESS)遗传力估计,以探讨吸烟行为与GERD之间的遗传相关性.然后，进行了一项联合的跨性状荟萃分析，以确定吸烟行为和GERD之间共有的“多效性SNP”，其次是共同定位分析。此外,使用注释（MAGMA）的多标记分析用于探索特定组织中单核苷酸多态性（SNP）遗传力的富集程度，基于汇总数据的孟德尔随机化（SMR）进一步用于研究潜在的功能基因。最后,进行孟德尔随机化（MR）分析以探讨吸烟行为与GERD之间的因果关系。
结果：通过全球和局部遗传相关性分析观察到一致的遗传相关性，其中SI，ES,CPD与GERD呈显著正相关，NS与ASI呈显著负相关。HESS分析还鉴定了它们之间的多个显著相关的基因座。此外，通过交叉性状荟萃分析和共定位分析鉴定了三个新的“多效性SNP”（rs4382592，rs200968，rs1510719），NS,ES,ASI,和GERD,定位基因MED27，HIST1H2BO，MAML3作为SI之间新的多效性基因，NS,ES,ASI,和GERD。此外，发现吸烟行为和GERD在多个脑组织中共同富集，使用GMPPB，RNF123和RBM6被鉴定为小脑半球共同富集的潜在功能基因，小脑,SI和GERD中的皮质/伏核，在尾状核中发现SUOX，小脑,NS和GERD中的皮质。最后,通过MR分析发现了一致的因果关系，表明SI，ES,CPD会增加GERD的风险，而NS和更高的ASI降低了风险。
结论：我们确定了与吸烟行为和GERD相关的遗传基因座，以及共享富集的脑组织部位，优先考虑三个新的多效性基因和四个新的功能基因。最后,证明了吸烟行为与GERD之间的因果关系，为GERD的早期预防策略提供见解。
方法：首先，我们进行了全局交叉性状遗传相关分析和汇总统计(HESS)遗传力估计,以探讨吸烟行为与GERD之间的遗传相关性.然后，进行了一项联合的跨性状荟萃分析，以确定吸烟行为和GERD之间共有的“多效性SNP”，其次是共同定位分析。此外,使用注释（MAGMA）的多标记分析用于探索特定组织中单核苷酸多态性（SNP）遗传力的富集程度，基于汇总数据的孟德尔随机化（SMR）进一步用于研究潜在的功能基因。最后,进行孟德尔随机化（MR）分析以探讨吸烟行为与GERD之间的因果关系。
结果：通过全球和局部遗传相关性分析观察到一致的遗传相关性，其中SI，ES,CPD与GERD呈显著正相关，NS与ASI呈显著负相关。HESS分析还鉴定了它们之间的多个显著相关的基因座。此外，通过交叉性状荟萃分析和共定位分析鉴定了三个新的“多效性SNP”（rs4382592，rs200968，rs1510719），NS,ES,ASI,和GERD,定位基因MED27，HIST1H2BO，MAML3作为SI之间新的多效性基因，NS,ES,ASI,和GERD。此外，发现吸烟行为和GERD在多个脑组织中共同富集，使用GMPPB，RNF123和RBM6被鉴定为小脑半球共同富集的潜在功能基因，小脑,SI和GERD中的皮质/伏核，在尾状核中发现SUOX，小脑,NS和GERD中的皮质。最后,通过MR分析发现了一致的因果关系，表明SI，ES,CPD会增加GERD的风险，而NS和更高的ASI降低了风险。
结论：我们确定了与吸烟行为和GERD相关的遗传基因座，以及共享富集的脑组织部位，优先考虑三个新的多效性基因和四个新的功能基因。最后,证明了吸烟行为与GERD之间的因果关系，为GERD的早期预防策略提供见解。
