Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Characteristics of patients with COVID-19 who have deteriorating chest X-ray findings within 48 hours: a retrospective cohort study (preprint)

Background The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). However, the prognostic impact of deterioration of CXR findings and the clinical characteristics of patients with worsening CXR findings remain unclear. We aimed to investigate the clinical and genetic characteristics, as well as the prognosis, of patients with worsening CXR findings during early hospitalisation.Methods We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission.Results Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases; high body temperature (≥ 37.7°C); and increased levels of serum aspartate aminotransferase (≥ 30 IU/L), potassium (≥ 4.3 mEq/L), and C-reactive protein (≥ 2.53 mg/dL) were independent risk factors for rapid deterioration of CXR findings. The risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients with COVID-19. Further, the population-specific risk variant at the DOCK2 locus (rs60200309-A) was nominally associated with rapid deterioration of CXR findings in patients aged < 65 years.Conclusions This study revealed the clinical features, genetic features, and risk factors for rapid deterioration of CXR findings in patients with COVID-19. Rapid deterioration of CXR findings is a poor prognostic factor for patients with COVID-19.

Association between ABO blood group/genotype and COVID-19 in a Japanese population (preprint)

Background: An association between coronavirus disease 2019 (COVID-19) and ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Additionally, little is known about the association between COVID-19 and ABO genotype. Therefore, the present study aimed to investigate the association between COVID-19 and ABO blood group/genotype in a large Japanese population. Methods: All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1,790 COVID-19 Japanese patients whose DNA was used for genome-wide association study. We compared the ABO blood group/genotype in healthy population (n = 611, control) and COVID-19 patients, and then analyzed the association between the ABO blood group/genotype and clinical outcomes. Results: Blood group A was significantly more prevalent (41.6% vs. 36.8%) and group O was significantly less prevalent (26.2% vs. 30.8%) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Further, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00–3.37)]. Similarly, in ABO genotype analysis, only genotype AB was an independent risk factor for most severe disease compared with genotype OO. Conclusions: Blood group O is protective, whereas blood group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of ‘most’ severe disease. 

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative (preprint)

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Regulatory T-cells are central hubs for age-, sex- and severity-associated cellular networks during COVID-19 (preprint)

Using single-cell proteomics by mass cytometry, we investigate changes to a broad selection of over 10,000,000 immune cells in a cohort of moderate, severe, and critical Japanese COVID-19 patients and healthy controls with a particular focus on regulatory T-cells (Tregs). We find significant disruption within all compartments of the immune system and the emergence of atypical CTLA-4high CD4 T-cells and proliferating HLA-DRlowCD38high Tregs associated with critical patients. We also observed disrupted regulation of humoral immunity in COVID-19, with a loss of circulating T follicular regulatory T cells (Tfr) and altered T follicular helper (Tfh)/Tfr and plasma cell/Tfr ratios, all of which are significantly lower in male patients. Shifting ratios of CXCR4 and CXCR5 expression in B-cells provides further evidence of an autoimmune phenotype and dysregulated humoral immunity. These results suggest that Tregs are central to the changing cellular networks of a wide range of cells in COVID-19 and that sex specific differences to the balance of Tfr, Tfh and plasma cells may have important implications for the specificity of the humoral immune response to SARS-CoV-2.

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan (preprint)

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.