Highlights An unbiased search across 974 phenotypic conditions, as well as genetic variants located in or near ACE2 and TMPRSS2 identified novel risk factors of severe COVID-19. Delirium, dementia, amnestic and other cognitive disorders increase the severe COVID-19 risk. Genetic variants in SARS‑CoV‑2 infection genes have suggestive evidence of association with severe COVID-19 and other phenotypes, such as immunity deficiency and prostate cancer. There is an urgent need for special dementia care during the COVID-19 pandemic.

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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.