Guanjie Chen, Lisa A DeRoo, Gabriel Goodney, Ayo P Doumatey, Jie Zhou, Adebowale A Adeyemo, Charles N Rotimi, Amadou Gaye
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The study includes African American adults from the GENE-FORECAST study, encompassing 371 individuals with whole genome sequencing (WGS), 203 with DNA methylation, and 321 with RNA sequencing (RNA-Seq) of blood. About 53.3% of participants reported COVID-19. Significant loci associated with COVID-19 were examined within the framework of methylation quantitative trait loci (mQTL), which are located near the gene-of-orig (<i>cis</i>-mQTL) and expression quantitative trait loci (eQTL), which are located near the gene-of-origin (<i>cis</i>-eQTL), enabling analysis to assess mediators between genetic variants and COVID-19 status. Our analysis identified four intronic variants and confirmed a missense variant, rs1052067, in <i>PMF1</i> associated with COVID-19. Causal mediation analysis revealed that the combination of genetic variants within <i>PMF1</i>, epigenomics, and transcriptomics mapped four pathways influencing COVID-19 status. These pathways include: rs9659072→DNAm at chr1:156285845 (annotated to <i>TMEM79</i>)→ENSG00000198715:13 (annotated to glycosylated lysosomal membrane protein, <i>GLMP</i>); rs12083543→DNAm at chr1:155951748 (<i>ARHGEF2</i>)→ENSG00000198715:13 (<i>GLMP</i>); rs1052067→DNAm at chr1:155951748 (<i>ARHGEF2</i>)→ENSG00000198715:13 (<i>GLMP</i>); rs1543294→ENSG00000198715:13 (<i>GLMP</i>)→DNAm at chr1:156077518 (<i>MEX3A</i>). Through integrated multiomics analyses, we identified genetic variants whose effects on COVID-19 susceptibility are mediated by changes in DNA methylation and mRNA expression. These findings offer insights into potential mechanistic pathways that merit further exploration.<b>NEW & NOTEWORTHY</b> The study investigates host genetic factors influencing COVID-19 susceptibility by integrating WGS, epigenomics, and transcriptomic data. It identified that PMF1 is linked to COVID-19. Mediation analysis revealed that genetic variants in PMF1 affect COVID-19 status via combinations of one transcript (annotated to GLMP) and three DNAm sites (annotated to ARHGEF2, TMEM79, MEX3A). The findings highlight the role of lysosomal pathways and transmembrane proteins in disease susceptibility, offering new insight into potential therapeutic targets for COVID-19.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. 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Heart and circulatory physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpheart.00206.2025","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
摘要
背景:引发2019年COVID-19大流行的SARS-CoV-2继续引发人们对宿主遗传因素在疾病易感性中的作用的研究。尽管发现了1000多个可能与SARS-CoV-2和COVID-19相关的基因,但将遗传变异与表型联系起来的机制仍然难以捉摸。为了阐明这些机制,我们进行了一项综合分析,将COVID-19的全基因组关联分析数据与甲基组和转录组分析相结合。方法:研究包括来自GENE-FORECAST研究的非裔美国成年人,包括371例全基因组测序(WGS), 203例DNA甲基化和321例血液RNA测序(RNA- seq)。53.3%的参与者报告了COVID-19。在位于原始基因(顺式-mQTL)附近的甲基化数量性状位点(mQTL)和位于原始基因(顺式-eQTL)附近的表达数量性状位点(eQTL)的框架内,研究了与COVID-19相关的重要位点,使分析能够评估遗传变异与COVID-19状态之间的介质。结果:我们的分析发现了4个内含子变异,并确认了与COVID-19相关的PMF1中的一个错义变异rs1052067。因果中介分析显示,PMF1内的遗传变异、表观基因组学和转录组学结合绘制了影响COVID-19状态的四种途径。这些通路包括:rs9659072 -> DNAm at chr1:156285845(注释到TMEM79) -> ENSG00000198715:13(注释到GLMP);rs12083543 -> DNAm at chr1:155951748 (ARHGEF2) -> ENSG00000198715:13 (GLMP);rs1052067 -> DNAm at chr1:155951748 (ARHGEF2)-> ENSG00000198715:13 (GLMP);rs1543294 -> ENSG00000198715:13 (GLMP) -> DNAm at chr1:156077518 (MEX3A)。结论:通过综合多组学分析,我们确定了影响COVID-19易感性的遗传变异是由DNA甲基化和mRNA表达变化介导的。这些发现为值得进一步探索的潜在机制途径提供了见解。
Multiomics analyses of the complex interplay between genetic variants, DNA methylation, and gene expression in COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which drove the 2019 coronavirus disease (COVID-19) pandemic, continues to engender inquiries into the role of host genetic factors in disease susceptibility. Despite the identification of over 1,000 genes potentially associated with SARS-CoV-2 and COVID-19, the mechanisms connecting genetic variants to phenotype remain elusive. To shed light on these mechanisms, we undertook an integrated analysis, merging data from whole genome association analyses of COVID-19 with methylome and transcriptomic. The study includes African American adults from the GENE-FORECAST study, encompassing 371 individuals with whole genome sequencing (WGS), 203 with DNA methylation, and 321 with RNA sequencing (RNA-Seq) of blood. About 53.3% of participants reported COVID-19. Significant loci associated with COVID-19 were examined within the framework of methylation quantitative trait loci (mQTL), which are located near the gene-of-orig (cis-mQTL) and expression quantitative trait loci (eQTL), which are located near the gene-of-origin (cis-eQTL), enabling analysis to assess mediators between genetic variants and COVID-19 status. Our analysis identified four intronic variants and confirmed a missense variant, rs1052067, in PMF1 associated with COVID-19. Causal mediation analysis revealed that the combination of genetic variants within PMF1, epigenomics, and transcriptomics mapped four pathways influencing COVID-19 status. These pathways include: rs9659072→DNAm at chr1:156285845 (annotated to TMEM79)→ENSG00000198715:13 (annotated to glycosylated lysosomal membrane protein, GLMP); rs12083543→DNAm at chr1:155951748 (ARHGEF2)→ENSG00000198715:13 (GLMP); rs1052067→DNAm at chr1:155951748 (ARHGEF2)→ENSG00000198715:13 (GLMP); rs1543294→ENSG00000198715:13 (GLMP)→DNAm at chr1:156077518 (MEX3A). Through integrated multiomics analyses, we identified genetic variants whose effects on COVID-19 susceptibility are mediated by changes in DNA methylation and mRNA expression. These findings offer insights into potential mechanistic pathways that merit further exploration.NEW & NOTEWORTHY The study investigates host genetic factors influencing COVID-19 susceptibility by integrating WGS, epigenomics, and transcriptomic data. It identified that PMF1 is linked to COVID-19. Mediation analysis revealed that genetic variants in PMF1 affect COVID-19 status via combinations of one transcript (annotated to GLMP) and three DNAm sites (annotated to ARHGEF2, TMEM79, MEX3A). The findings highlight the role of lysosomal pathways and transmembrane proteins in disease susceptibility, offering new insight into potential therapeutic targets for COVID-19.
期刊介绍:
The American Journal of Physiology-Heart and Circulatory Physiology publishes original investigations, reviews and perspectives on the physiology of the heart, vasculature, and lymphatics. These articles include experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact and integrative animal and organ function to the cellular, subcellular, and molecular levels. The journal embraces new descriptions of these functions and their control systems, as well as their basis in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new mechanistic physiological insights that determine the performance of the normal and abnormal heart and circulation.