冠心病和慢性阻塞性肺疾病多效性基因识别的跨组学整合研究

Integrative cross-omics analysis identifies pleiotropic genes shared by coronary artery disease and chronic obstructive pulmonary disease

摘要

目的 整合全转录组关联分析和复合零假设下的多效性分析,从转录组学层面探讨冠心病(coronary artery disease, CAD)-慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)潜在的多效性基因,为深入了解CAD-COPD的共病机制提供新见解。 方法 利用来源于美国退伍军人事务部百万退伍军人计划的CAD和COPD的全基因组关联研究(genome-wide association study, GWAS)汇总数据以及来源于GTEx V8的外周全血数据,采用FUSION进行全转录组关联分析,并利用gPLACO方法分析CAD-COPD潜在的多效性基因。对识别出的多效性基因进行富集分析、蛋白质-蛋白质相互作用网络分析和孟德尔随机化分析,并基于GEO数据库验证多效性基因的差异表达。 结果 经Benjamini-Hochberg校正后,FUSION共识别出794个CAD相关基因及463个COPD相关基因。gPLACO识别出79个CAD-COPD多效性基因,其中,62个多效性基因在CAD和COPD的TWAS结果中同时显著。GO富集分析和转录因子靶基因富集结果揭示了CAD-COPD潜在的生物学通路,包括肉碱跨膜转运活性(P=6.03×10^-7)和MEF2C靶基因(P=5.01×10^-3)。多效性基因STARD3在蛋白质-蛋白质相互作用网络分析、孟德尔随机化分析以及差异表达基因分析中得到了进一步验证。 结论 STARD3可以作为潜在的CAD-COPD多效性基因;肉碱代谢和内皮功能在CAD-COPD共病中具有重要作用。

Abstract

Objective To integrate transcriptome-wide association studies(TWAS)with pleiotropy analysis under a composite null hypothesis and to explore potential pleiotropic genes for coronary artery disease(CAD)and chronic obstructive pulmonary disease(COPD)from a transcriptomic perspective, providing new insights into the comorbid mechanisms of CAD and COPD. Methods Genome-wide association study(GWAS)summary data for CAD and COPD were obtained from the Million Veteran Program of The Department of Veterans Affairs, and gene expression reference weights for whole blood were derived from GTEx V8. TWAS was conducted using FUSION, and potential pleiotropic genes for CAD and COPD were analyzed using the gPLACO method developed in this study. Furthermore, enrichment analysis, protein-protein interaction analysis, Mendelian randomization analysis, and differential gene expression analysis were conducted on the CAD-COPD pleiotropic genes. Results After Benjamini-Hochberg correction, FUSION identified a total of 794 genes associated with CAD and 463 genes associated with COPD. gPLACO identified 79 pleiotropic genes shared between CAD and COPD, of which 62 were simultaneously significant in TWAS results for both diseases. GO enrichment analysis and transcription factor target gene enrichment further revealed potential biological pathways underlying CAD-COPD comorbidity, including carnitinetransmembrane transporter activity(P=6.03×10^-7)and MEF2C target gene(P=5.01×10^-3). Further protein-protein interaction analysis, Mendelian randomization analysis, and differential gene expression analysis also suggested STARD3 as a potential pleiotropic gene for CAD-COPD. Conclusion STARD3 is a potential pleiotropic gene for CAD-COPD, underscoring the critical roles of carnitine metabolism and endothelial function in their shared pathophysiology.

关键词

冠心病 / 慢性阻塞性肺疾病 / 多效性基因 / 跨组学数据整合 / 全转录组关联分析

Key words

Coronary artery disease / Chronic obstructive pulmonary disease / Pleiotropic genes / Multi-omics data integration / Transcriptome-wide association study

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基金资助

国家自然科学基金(82373686)

中央高校青年教师科研创新能力支持项目(SRICSPYF-ZY2025123)

山东省自然科学基金(ZR2024JQ029)

山东省泰山学者项目(tsqn202211025)