Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Julie Horowitz, Jack A. Kosmicki, Amy Damask, Deepika Sharma, Genevieve H. L. Roberts, Anne E. Justice, Nilanjana Banerjee, Marie V. Coignet, Ashish Yadav, Joseph B. Leader, Anthony Marcketta, Danny S. Park, Rouel Lanche, Evan K. Maxwell, Spencer C. Knight, Xiaodong Bai, Harendra Guturu, Dylan Sun, Asher K. Haug Baltzell, Fabrício S. P. Kury, Joshua Backman, Ahna R. Girshick, Colm O’Dushlaine, Shannon McCurdy, Raghavendran Partha, Adam J. Mansfield, David A. Turissini, Alexander Li, Miao Zhang, Joelle Mbatchou, Kyoko Watanabe, Lauren Gurski, Shane McCarthy, Hyun Min Kang, Lee Dobbyn, Eli A. Stahl, Anurag Verma, Giorgio Sirugo, RGC Management and Leadership Team, Gonçalo R. Abecasis, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris N. Economides, Katia Karalis, Luca A. Lotta, Alan R. Shuldiner, Sequencing and Lab Operations, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D. Schleicher, Louis Widom, Sarah E. Wolf, Ricardo H. Ulloa, Amelia Averitt, Dadong Li, Sameer Malhotra, Jeffrey Staples, Genome Informatics, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Evan K. Maxwell, George Mitra, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, Jeffrey G. Reid, William Salerno, Jeffrey Staples, Kathie Sun, Jiwen Xin, Analytical Genomics and Data Science, Joshua Backman, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher E. Gillies, Eric Jorgenson, Hyun Min Kang, Michael D. Kessler, Alexander Li, Nan Lin, Daren Liu, Adam E. Locke, Arden Moscati
Abstract
Abstract 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.