Genomewide Association Study of Severe Covid-19 with Respiratory Failure

Abstract

BACKGROUNDThere is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 . Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. METHODSWe conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels. RESULTSWe detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10 −8 ) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10 −10 ; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10 −8 , respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10 −4 ) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10 −5 ). CONCLUSIONSWe identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19

“…With this in mind, even though the collected knowledge is still limited to few studies, some susceptibility markers other than HLA have been proposed for Covid-19. An association with ABO blood antigens has been observed in a cohort of Chinese patients, with the type A and 0 being respectively at highest and lowest risk to be infected, as previously been reported for other viral infections [36,37]. Genetic polymorphisms of key genes of the virus entry machinery (Ace2, Tmprss2, CtsB, and CtsL) or of the in ammatory/immune response (e.g.…”

The Trans-omics Landscape of COVID-19

“…For rs657152, the overall frequency of the protective allele C was 0.5468 (222/406) in our data, with the lowest rate found in the critical group (AF = 0.382, 13/34, Fisher's exact test P = 0.04896). For rs11385942, the risk allele GA was not detected in any patient in our study, as this variant was rare in Chinese people 27 (Supplementary Table 4.4), consistent with previously reported global distribution 26 . Quantitative trait locus (QTL) analysis has been widely applied to infer the contribution of genetic variations to complex phenotypes 28 .…”

“…Additionally, PTGIS possesses anti-in ammatory properties by modulating the expression of IL-1, IL-6, IL-10, which may be associated with the COVID-19 severity 25 . We also assessed two loci, rs657152 at locus 9q34.2 and rs11385942 at locus 3p21.31, which have been found to be associated with COVID-19 patients with severe respiratory failure in Spanish and Italian populations 26 . For rs657152, the overall frequency of the protective allele C was 0.5468 (222/406) in our data, with the lowest rate found in the critical group (AF = 0.382, 13/34, Fisher's exact test P = 0.04896).…”

Deciphering the state of immune silence in fatal COVID-19 patients

“…rs11385942 may act trough the regulation of the memory lymphoid cell migration Expression pro les generated by scRNA-seq can be overlaid with genome-wide association studies (GWASs) to pinpoint speci c cell types and identify potential cellular and molecular mechanisms explaining the described genetic associations [28]. In addition to the ABO group locus, a recent study found that another genomic locus is associated with the development of severe forms of COVID-19 [23].…”

“…Unfortunately, none of the past studies analyzed the immune regulatory properties of myeloid cells at functional level. A speci c genetic locus including immune related genes (such as C-X-C motif chemokine receptor 6 -CXCR6), was found to be associated with worse prognosis in COVID-19 patients [23]. Other studies exclusively performed on broncho-alveolar lavage uids (BAL), elucidated the sustained interplay between macrophages releasing in ammatory cytokines and lung epithelial cells in more severe COVID-19 disease stages [21], whereas pointed out highly clonally expanded CD8 + T cells in moderate patients [22].…”