Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10−8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10−13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome-sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19; (ii) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

We present Doc2Hpo, an interactive web application that enables interactive and efficient phenotype concept curation from clinical text with automated concept normalization using the Human Phenotype Ontology (HPO). Users can edit the HPO concepts automatically extracted by Doc2Hpo in real time, and export the extracted HPO concepts into gene prioritization tools. Our evaluation showed that Doc2Hpo significantly reduced manual effort while achieving high accuracy in HPO concept curation. Doc2Hpo is freely available at https://impact2.dbmi.columbia.edu/doc2hpo/. The source code is available at https://github.com/stormliucong/doc2hpo for local installation for protected health data.

Purpose To assess the relative risk of Alzheimer's disease (AD) among patients with prostate cancer who received androgen deprivation therapy (ADT), after adjustment for other cancer therapies. Methods Data from demographics, survival, diagnoses codes, procedure codes, and other information about beneficiaries age 67 years or older in the Medicare claims database was assessed to determine the unadjusted and adjusted risks of AD and of dementia from ADT. The prespecified survival analysis method was competing risk regression. Results Of the 1.2 million fee-for-service Medicare beneficiaries who developed prostate cancer in 2001 to 2014, 35% received ADT. Of these, 109,815 (8.9%) and 223,765 (18.8%) developed AD and dementia, respectively, and 26% to 33% died without either outcome. Unadjusted rates of AD and all-cause mortality per 1,000 patient-years were higher among ADT recipients; the unadjusted rates of AD were 17.0 and 15.5 per 1,000 person-years in recipients and nonrecipients, respectively, and the unadjusted rates of all-cause mortality were 73.0 and 51.6 per 1,000 person-years, respectively. The unadjusted rates for dementia in ADT recipients versus nonrecipients were 38.5 and 32.9, respectively, and the unadjusted rates of mortality were 60.2 versus 40.4, respectively. However, after analysis was adjusted for other cancer therapies and other covariates, patients with ADT treatment had no increased risk of AD (subdistribution hazard ratio [SHR], 0.98; 95% CI, 0.97 to 0.99) and had only a miniscule (1%) risk of dementia (SHR, 1.01; 95% CI, 1.01 to 1.02); patients treated with ADT were more likely to die before progression to AD (SHR, 1.24; 95% CI, 1.23 to 1.24) or dementia (SHR, 1.26; 95% CI, 1.25 to 1.26). The risks of AD and dementia were not associated with duration of ADT (ie, no dose effect). Other secondary analyses confirmed these results. Conclusion These data suggest that ADT treatment has no hazard for AD and no meaningful hazard for dementia among men age 67 years or older who are enrolled in Medicare.

The need to identify and effectively treat COVID-19 cases at highest risk for severe disease is critical. We identified seven common genetic variants (three novel) that modulate COVID-19 susceptibility and severity, implicating IFNAR2, CCHCR1, TCF19, SLC6A20 and the hyaluronan pathway as potential therapeutic targets. A high genetic burden was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known risk factors.