Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Authors: Julie E. 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 Maxwell, Spencer C. Knight, Xiaodong Bai, Harendra Guturu, Dylan Sun, Asher Baltzell, Fabricio S. P. Kury, Joshua D. Backman, Ahna R. Girshick, Colm O’Dushlaine, Shannon R. McCurdy, Raghavendran Partha, Adam J. Mansfield, David A. Turissini, Alexander H. Li, Miao Zhang, Joelle Mbatchou, Kyoko Watanabe, Lauren Gurski, Shane E. McCarthy, Hyun M. Kang, Lee Dobbyn, Eli Stahl, Anurag Verma, Giorgio Sirugo, Gonçalo Abecasis, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A. Lotta, Alan Shuldiner, 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, 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 C. Staples, Kathie Sun, Jiwen Xin, Joshua Backman, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Arden Moscati, Charles Paulding, Carlo Sidore, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Ariane Ayer, Aysegul Guvenek, George Hindy, Jan Freudenberg, Jonas Bovijn, Julie E. Horowitz, Kavita Praveen, Manav Kapoor, Mary Haas, Moeen Riaz, Niek Verweij, Olukayode Sosina, Parsa Akbari, Priyanka Nakka, Sahar Gelfman, Sujit Gokhale, Tanima De, Veera Rajagopal, Gannie Tzoneva, Juan Rodriguez-Flores, Shek Man Chim, Valerio Donato, Daniel Fernandez, Giusy Della Gatta, Alessandro Di Gioia, Kristen Howell, Lori Khrimian, Minhee Kim, Hector Martinez, Lawrence Miloscio, Sheilyn Nunez, Elias Pavlopoulos, Trikaldarshi Persaud, Esteban Chen, Marcus B. Jones, Michelle G. LeBlanc, Jason Mighty, Lyndon J. Mitnaul, Nirupama Nishtala, Nadia Rana, Marylyn D. Ritchie, Marcus Jones, Suganthi Balasubramanian, Katherine Siminovitch, William J. Salerno, Alan R. Shuldiner, Daniel J. Rader, Tooraj Mirshahi, Adam E. Locke, Jonathan Marchini, John D. Overton, David J. Carey, Lukas Habegger, Michael N. Cantor, Kristin A. Rand, Eurie L. Hong, Jeffrey G. Reid, Catherine A. Ball, Aris Baras, Gonçalo R. Abecasis, Manuel A. R. Ferreira
Journal: Nature Genetics (2022)

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.