Ruß Anne-Kathrin, Schreiber Stefan, Lieb Wolfgang, Vehreschild J Janne, Heuschmann Peter U, Illig Thomas, Appel Katharina S, Vehreschild Maria J G T, Krefting Dagmar, Reinke Lennart, Viebke Alin, Poick Susanne, Störk Stefan, Reese Jens-Peter, Zoller Thomas, Krist Lilian, Ellinghaus David, Foesel Bärbel U, Gieger Christian, Lorenz-Depiereux Bettina, Witzenrath Martin, Anton Gabriele, Krawczak Michael, Heyckendorf Jan, Bahmer Thomas
Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Brunswiker Straße 10, 24113, Kiel, Germany.
Institute of Epidemiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
Sci Rep. 2025 May 6;15(1):15791. doi: 10.1038/s41598-025-00945-z.
If health impairments due to coronavirus disease 2019 (COVID-19) persist for 12 weeks or longer, patients are diagnosed with Post-COVID Syndrome (PCS), or Long-COVID. Although the COVID-19 pandemic has largely subsided in 2024, PCS is still a major health burden worldwide, and identifying potential genetic modifiers of PCS remains of great clinical and scientific interest. We therefore performed a case-control type genome-wide association study (GWAS) of three recently developed PCS (severity) scores in 2,247 participants of COVIDOM, a prospective, multi-centre, population-based cohort study of SARS-CoV-2-infected individuals in Germany. Each PCS score originally represented the weighted sum of the binary indicators of all, or a subset, of 12 PCS symptom complexes, assessed six months or later after the PCR test-confirmed SARS-CoV-2 infection of a participant. For various methodical reasons, however, the PCS scores were dichotomized along their respective median values in the present study, prior to the GWAS. Of the 6,383,167 single nucleotide polymorphisms included, various variants were found to be associated with at least one of the PCS scores, although not at the stringent genome-wide statistical significance level of 5 × 10. With p = 6.6 × 10, however, the genotype-phenotype association of SNP rs9792535 at position chr9:127,166,653 narrowly missed this threshold. The SNP is located in a region including the NEK6, PSMB7 and ADGRD2 genes which, however, does not immediately suggest an etiological connection to PCS. As regards functional plausibility, variants of a possible effect mapped to the olfactory receptor gene region (lead SNP rs10893121 at position chr11:123,854,744; p = 2.5 × 10). Impairment of smell and taste is a pathognomonic feature of both, acute COVID-19 and PCS, and our results suggest that this connection may have a genetic basis. Three other genotype-phenotype associations pointed towards a possible etiological role in PCS of cellular virus repression (CHD6 gene region), activation of macrophages (SLC7A2) and the release of virus particles from infected cells (ARHGAP44). All other gene regions highlighted by our GWAS did not relate to pathophysiological processes currently discussed for PCS. Therefore, and because the genotype-phenotype associations observed in our GWAS were generally not very strong, the complexity of the genetic background of PCS appears to be as high as that of most other multifactorial traits in humans.
如果2019冠状病毒病（COVID-19）导致的健康损害持续12周或更长时间，患者将被诊断为新冠后综合征（PCS），即长新冠。尽管COVID-19大流行在2024年已基本平息，但PCS仍是全球主要的健康负担，确定PCS的潜在基因修饰因子仍具有重大的临床和科学意义。因此，我们对德国一项针对感染严重急性呼吸综合征冠状病毒2型个体的前瞻性、多中心、基于人群的队列研究COVIDOM中的2247名参与者，进行了一项病例对照型全基因组关联研究（GWAS），研究对象为最近开发的三个PCS（严重程度）评分。每个PCS评分最初代表12个PCS症状复合体全部或部分二元指标的加权总和，这些症状复合体在参与者经PCR检测确诊感染SARS-CoV-2六个月或更久之后进行评估。然而，由于各种方法学原因，在本研究的GWAS之前，PCS评分根据各自的中位数进行了二分法划分。在纳入的6383167个单核苷酸多态性中，发现各种变体与至少一个PCS评分相关，尽管未达到严格意义上的全基因组统计学显著性水平5×10。然而，位于chr9:127166653位置的单核苷酸多态性rs9792535的基因型-表型关联以p = 6.6×10勉强未达到该阈值。该单核苷酸多态性位于一个包含NEK6、PSMB7和ADGRD2基因的区域，但这并未立即表明与PCS存在病因学联系。关于功能合理性，一个可能产生影响的变体映射到嗅觉受体基因区域（位于chr11:123854744位置的主效单核苷酸多态性rs10893121；p = 2.5×10）。嗅觉和味觉减退是急性COVID-19和PCS的一个特征性表现，我们的结果表明这种联系可能有遗传基础。另外三个基因型-表型关联表明，细胞病毒抑制（CHD6基因区域）、巨噬细胞激活（SLC7A2）以及病毒颗粒从受感染细胞中释放（ARHGAP44）在PCS中可能具有病因学作用。我们的GWAS突出显示的所有其他基因区域均与目前针对PCS讨论的病理生理过程无关。因此，由于我们的GWAS中观察到的基因型-表型关联通常不是很强，PCS遗传背景的复杂性似乎与人类大多数其他多因素性状一样高。
