Journal Article

Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

Jones, Marcus, McCarthy, Shane E., Park, Danny S., Abecasis, Gonçalo R., Knight, Spencer C., Hong, Eurie L., Kosmicki, Jack A., Overton, John D., Banerjee, Nilanjana, Coignet, Marie V., Baltzell, Asher, Turissini, David A., Leader, Joseph B., Backman, Joshua D., Locke, Adam E., O’Dushlaine, Colm, Zhang, Miao, Ferreira, Manuel A. R., Sharma, Deepika, Mansfield, Adam J., Salerno, William J., Cantor, Michael N., Rader, Daniel J., Baras, Aris, Marcketta, Anthony, Ritchie, Marylyn D., Yadav, Ashish, Habegger, Lukas, Reid, Jeffrey G., Guturu, Harendra, Kury, Fabricio S. P., Carey, David J., Gurski, Lauren, Li, Alexander H., Shuldiner, Alan R., Mirshahi, Tooraj, Verma, Anurag, Sirugo, Giorgio, Roberts, Genevieve H. L., Watanabe, Kyoko, Damask, Amy, Bai, Xiaodong, Justice, Anne E., Kang, Hyun M., Sun, Dylan, Balasubramanian, Suganthi, Mbatchou, Joelle, Horowitz, Julie E., McCurdy, Shannon R., Ball, Catherine A., Lanche, Rouel, Maxwell, Evan, Partha, Raghavendran, Marchini, Jonathan, Girshick, Ahna R., Siminovitch, Katherine, Rand, Kristin A., Dobbyn, Lee, Stahl, Eli

2022

Overview

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. Genome-wide meta-analysis of SARS-CoV-2 susceptibility and severity phenotypes in up to 756,646 samples identifies a rare protective variant proximal to ACE2 . A 6-SNP genetic risk score provides additional predictive power when added to known risk factors.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 631/208/457 / ACE2 / Agriculture / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Animal Genetics and Genomics / Biobanks / Biomedical and Life Sciences / Biomedicine / Blood pressure / Cancer Research / Chronic obstructive pulmonary disease / Coronaviruses / COVID-19 / COVID-19 - genetics / Enzymes / Gene expression / Gene frequency / Gene Function / Genetic analysis / Genome-wide association studies / Genome-Wide Association Study / Genomes / Health risk assessment / Hospitalization / Human Genetics / Humans / Infections / Peptidyl-dipeptidase A / Respiratory diseases / Risk / Risk Factors / SARS-CoV-2 - genetics / Severe acute respiratory syndrome coronavirus 2 / Viral diseases / Viral infections