Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Authors: Horowitz Julie E. , Kosmicki Jack A. , Damask Amy , Sharma Deepika , Roberts Genevieve H. L. , Justice Anne E. , Banerjee Nilanjana , Coignet Marie V. , Yadav Ashish , Leader Joseph B. , Marcketta Anthony , Park Danny S. , Lanche Rouel , Maxwell Evan , Knight Spencer C. , Bai Xiaodong , Guturu Harendra , Sun Dylan , Baltzell Asher , Kury Fabricio S. P. , Backman Joshua D. , Girshick Ahna R. , O’Dushlaine Colm , McCurdy Shannon R. , Partha Raghavendran , Mansfield Adam J. , Turissini David A. , Li Alexander H. , Zhang Miao , Mbatchou Joelle , Watanabe Kyoko , Gurski Lauren , McCarthy Shane E. , Kang Hyun M. , Dobbyn Lee , Stahl Eli , Verma Anurag , Sirugo Giorgio ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Abecasis Gonçalo , Cantor Michael , Coppola Giovanni , Deubler Andrew , Economides Aris , Karalis Katia , Lotta Luca A. , Shuldiner Alan ,   Sequencing and Lab Operations, Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Padilla Maria Sotiropoulos , Pradhan Manasi , Manoochehri Kia , Schleicher Thomas D. , Widom Louis , Wolf Sarah E. , Ulloa Ricardo H. ,   Clinical Informatics, Averitt Amelia , Li Dadong , Malhotra Sameer , Staples Jeffrey ,   Genome Informatics, Bao Suying , Boutkov Boris , Chen Siying , Eom Gisu , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Maxwell Evan K. , Mitra George , Nafde Mona , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Reid Jeffrey G. , Salerno William , Staples Jeffrey C. , Sun Kathie , Xin Jiwen ,   Analytical Genomics and Data Science, Backman Joshua , Ferreira Manuel Allen Revez , Ghosh Arkopravo , Gillies Christopher , Jorgenson Eric , Kang Hyun Min , Kessler Michael , Li Alexander , Lin Nan , Liu Daren , Locke Adam , Moscati Arden , Paulding Charles , Sidore Carlo , Ye Bin , Zhang Blair , Ziyatdinov Andrey ,   Therapeutic Area Genetics, Ayer Ariane , Guvenek Aysegul , Hindy George , Freudenberg Jan , Bovijn Jonas , Horowitz Julie E. , Praveen Kavita , Kapoor Manav , Haas Mary , Riaz Moeen , Verweij Niek , Sosina Olukayode , Akbari Parsa , Nakka Priyanka , Gelfman Sahar , Gokhale Sujit , De Tanima , Rajagopal Veera , Tzoneva Gannie , Rodriguez-Flores Juan ,   RGC Biology, Chim Shek Man , Donato Valerio , Fernandez Daniel , Gatta Giusy Della , Di Gioia Alessandro , Howell Kristen , Khrimian Lori , Kim Minhee , Martinez Hector , Miloscio Lawrence , Nunez Sheilyn , Pavlopoulos Elias , Persaud Trikaldarshi ,   Research Program Management & Strategic Initiatives, Chen Esteban , Jones Marcus B. , LeBlanc Michelle G. , Mighty Jason , Mitnaul Lyndon J. , Nishtala Nirupama , Rana Nadia , Ritchie Marylyn D. , Jones Marcus , Balasubramanian Suganthi , Siminovitch Katherine , Salerno William J. , Shuldiner Alan R. , Rader Daniel J. , Mirshahi Tooraj , Locke Adam E. , Marchini Jonathan , Overton John D. , Carey David J. , Habegger Lukas , Cantor Michael N. , Rand Kristin A. , Hong Eurie L. , Reid Jeffrey G. , Ball Catherine A. , Baras Aris , Abecasis Gonçalo R. , Ferreira Manuel A. R. 
Published: March 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.