Extensive Mendelian randomization study identifies potential causal risk factors for severe COVID-19.

Background: Identifying causal risk factors for severe coronavirus disease 2019 (COVID-19) is critical for its prevention and treatment. Many associated pre-existing conditions and biomarkers have been reported, but these observational associations suffer from confounding and reverse causation. Methods: Here, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19. Results: Our results highlight multiple body mass index (BMI)-related traits as risk-increasing: BMI (OR: 1.89, 95% CI: 1.51-2.37), hip circumference (OR: 1.46, 1.15-1.85), and waist circumference (OR: 1.82, 1.36-2.43). Our multivariable MR analysis further suggests that the BMI-related effect might be driven by fat mass (OR: 1.63, 1.03-2.58), but not fat-free mass (OR: 1.00, 0.61-1.66). Several white blood cell counts are negatively associated with severe COVID-19, including those of neutrophils (OR: 0.76, 0.61-0.94), granulocytes (OR: 0.75, 0.601-0.93), and myeloid white blood cells (OR: 0.77, 0.62-0.96). Furthermore, some circulating proteins are associated with an increased risk of (e.g., zinc-alpha-2-glycoprotein) or protection from severe COVID-19 (e.g., prostate-associated microseminoprotein). Conclusions: Our study suggests that fat mass and white blood cells might be involved in the development of severe COVID-19. It also prioritizes potential risk and protective factors that might serve as drug targets and guide the effective protection of high-risk individuals.

White Blood Cells and Severe COVID-19: A Mendelian Randomization Study.

Increasing evidence shows that white blood cells are associated with the risk of coronavirus disease 2019 (COVID-19), but the direction and causality of this association are not clear. To evaluate the causal associations between various white blood cell traits and the COVID-19 susceptibility and severity, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses with summary statistics from the largest and most recent genome-wide association studies. Our MR results indicated causal protective effects of higher basophil count, basophil percentage of white blood cells, and myeloid white blood cell count on severe COVID-19, with odds ratios (OR) per standard deviation increment of 0.75 (95% CI: 0.60-0.95), 0.70 (95% CI: 0.54-0.92), and 0.85 (95% CI: 0.73-0.98), respectively. Neither COVID-19 severity nor susceptibility was associated with white blood cell traits in our reverse MR results. Genetically predicted high basophil count, basophil percentage of white blood cells, and myeloid white blood cell count are associated with a lower risk of developing severe COVID-19. Individuals with a lower genetic capacity for basophils are likely at risk, while enhancing the production of basophils may be an effective therapeutic strategy.

White Blood Cells and Severe COVID-19: A Mendelian Randomization Study

Increasing evidence shows that white blood cells are associated with the risk of coronavirus disease 2019 (COVID-19), but the direction and causality of this association are not clear. To evaluate the causal associations between various white blood cell traits and the COVID-19 susceptibility and severity, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses with summary statistics from the largest and most recent genome-wide association studies. Our MR results indicated causal protective effects of higher basophil count, basophil percentage of white blood cells, and myeloid white blood cell count on severe COVID-19, with odds ratios (OR) per standard deviation increment of 0.75 (95% CI: 0.60–0.95), 0.70 (95% CI: 0.54–0.92), and 0.85 (95% CI: 0.73–0.98), respectively. Neither COVID-19 severity nor susceptibility was associated with white blood cell traits in our reverse MR results. Genetically predicted high basophil count, basophil percentage of white blood cells, and myeloid white blood cell count are associated with a lower risk of developing severe COVID-19. Individuals with a lower genetic capacity for basophils are likely at risk, while enhancing the production of basophils may be an effective therapeutic strategy.

Cognitive disorders associated with hospitalization of COVID-19: Results from an observational cohort study.

INTRODUCTION: Our understanding of risk factors for COVID­19, including pre-existing medical conditions and genetic variations, is limited. To what extent the pre-existing clinical condition and genetic background have implications for COVID-19 still needs to be explored. METHODS: Our study included 389,620 participants of European descent from the UK Biobank, of whom 3,884 received the COVID-19 test and 1,091 were tested positive for COVID-19. We examined the association of COVID-19 status with an extensive list of 974 medical conditions and 30 blood biomarkers. Additionally, we tested the association of genetic variants in two key genes related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), with COVID-19 or any other phenotypes. RESULTS: The most significant risk factors for COVID-19 include Alzheimer's disease (OR = 2.29, 95% CI: 1.25-4.16), dementia (OR = 2.16, 95% CI: 1.36-3.42), and the overall category of delirium, dementia, amnestic and other cognitive disorders (OR = 1.90, 95% CI: 1.24-2.90). Evidence suggesting associations of genetic variants in SARS-CoV-2 infection-related genes with COVID-19 (rs7282236, OR = 1.33, 95% CI: 1.14-1.54, p = 2.31 × 10-4) and other phenotypes, such as an immune deficiency (p = 5.65 × 10-5) and prostate cancer (p = 1.1 × 10-5), was obtained. CONCLUSIONS: Our unbiased and extensive search identified pre-existing Alzheimer's disease and dementia as top risk factors for hospital admission due to COVID-19, highlighting the importance of providing special protective care for patients with cognitive disorders during this pandemic. We also obtained evidence suggesting a direct association of genetic variants with COVID-19.

Altered Blood Cell Traits Underlie a Major Genetic Locus of Severe COVID-19.

BACKGROUND: The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. METHODS: To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample. RESULTS: Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10-8, 4.09 × 10-13), eosinophil count and percentage (p = 5.73 × 10-3, 2.20 × 10-3), and neutrophil percentage (p = 3.23 × 10-3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10-21, 5.08 × 10-19); CCR2 with monocytes (p = 2.40 × 10-10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10-6, 7.17 × 10-5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. CONCLUSIONS: Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.

SARS-CoV-2 Receptor ACE2 Is Enriched in a Subpopulation of Mouse Tongue Epithelial Cells in Nongustatory Papillae but Not in Taste Buds or Embryonic Oral Epithelium.

As a result of the COVID-19 pandemic, evidence revealed that SARS-CoV-2 infection caused taste loss at a rate higher than that of influenza. ACE2, the entry receptor of SARS-CoV-2, has been identified in the oral epithelium; however, it is unclear at what developmental stage ACE2 expression emerges and whether ACE2 is expressed in taste buds. To identify the specific developmental stage, we analyzed RNA-Seq data from embryonic and newborn mouse oral tissue. We found that robust ACE2 expression was observed in the newborn oral epithelium. In contrast, only extremely low levels, if any, of ACE2 transcripts in the embryonic stage oral tissue were found (E12.5 and E14.5). Analyses of three public scRNA-seq data sets of adult mouse tongue epithelial cells showed that receptors for various viruses were enriched in distinct clusters of tongue epithelial cells. ACE2 was enriched in a subpopulation of epithelial cells in the basal region of nongustatory filiform papillae but not in the taste papillae or taste buds. Expression of ACE2 was detected in a small proportion of type III taste cells. Our results indicate that when applied across species, nongustatory papilla epithelial cells are the prime targets for SARS-CoV-2 infection in the tongue; thus, taste loss in COVID-19 patients is likely not caused by a direct infection of SARS-CoV-2 to taste bud cells. Additionally, fetuses at different stages of development may have distinct susceptibility to SARS-CoV-2 infection.