GWAS of Severe COVID-19 With Respiratory Failure

Quick Takes

  • Polymorphisms in two gene clusters were found to be associated with severe COVID-19; one comprising genes involved in the regulation of the immune response, and the other determining the ABO blood groups.
  • The GWAS findings confirm prior reports of patients with blood type A being at higher risk for severe COVID-19, and those with blood type O being protected.
  • Much work remains to be done to establish the usefulness of genetic testing for COVID-19.

Study Questions:

What are the genetic variants associated with severe coronavirus disease 2019 (COVID-19)?


The authors conducted a case-control genomewide association study (GWAS) involving 1,980 patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe disease defined as the need for oxygen supplementation or mechanical ventilation at any point during the hospitalization. Patients were enrolled from three hospitals in Italy (n = 835) and four hospitals in Spain (n = 775). The control group consisted of 2,381 participants including randomly selected blood donors and healthy volunteers. The clinical data available were limited to age, gender, hypertension, diabetes mellitus, and whether the patient required oxygen supplementation alone or mechanical ventilation.


The median age of the patients with COVID-19 was approximately 65 years. Women consisted of 35% of the cohort. The rates of mechanical ventilation varied dramatically by center, ranging from 15-69%. Approximately 20% of patients had diabetes mellitus and 45% had hypertension. The authors identified two loci associated with severe COVID-19: rs11385942 insertion–deletion GA or G variant at locus 3p21.31 (comprising SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1) (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48-2.11) and the rs657152 A or C single nucleotide polymorphism (SNP) at locus 9q34.2 (ABO blood group) (OR, 1.32; 95% CI, 1.20-1.47), which persisted after adjusting for age and sex, and consistent when examining Spanish and Italian separately. The risk allele GA of rs11385942 is associated with reduced expression of CXCR6 and increased expression of SLC6A20, and LZTFL1 is strongly expressed in human lung cells. With regards to ABO blood group locus, the authors found a higher risk among persons with blood group A than among patients with other blood groups (OR, 1.45; 95% CI, 1.20-1.75) and a protective effect for blood group O as compared with the other blood groups (OR, 0.65; 95% CI, 0.53-0.79). There were SNP association signals in the HLA regions, known to have an important role in severe viral infections.


Polymorphisms in two gene clusters were found to be associated with severe COVID-19: locus 3p21.31 (comprising SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, and XCR1) and locus 9q34.2 (ABO blood group), with blood group A conferring a higher risk, while blood group O having a protective effect.


The inability to reliably determine who is susceptible to severe manifestations of SARS-CoV-2 has posed a tremendous challenge to all aspects of health policy including infection control measures and re-opening the economy. While older age, obesity, male sex, hypertension, and diabetes mellitus have been established as risk factors for severe COVID-19, they do not account for the significant number of otherwise healthy individuals who develop fulminant cytokine release and multiorgan failure with COVID-19. The study’s main limitation is in its control group being healthy individuals, rather than SARS-CoV-2 infected individuals that are asymptomatic. Nevertheless, the study confirms the existence of genetic predispositions to severe COVID-19, which involve the locus for ABO blood groups (9q34.2) and a locus of genes (3p21.31) related to the regulation of the ACE2 receptor and immune response. While these findings may help guide mechanistic studies into the biology of COVID-19, there is still much work to do before establishing the usefulness of genetic testing in managing the pandemic.

Clinical Topics: Prevention, Hypertension

Keywords: Alleles, Blood Group Antigens, Coronavirus, COVID-19, Cytokines, Diabetes Mellitus, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Hypertension, Infection Control, Polymorphism, Single Nucleotide, Primary Prevention, Respiration, Artificial, SARS Virus

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