학술논문
Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Document Type
Article
Author
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; 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.
Source
Nature Genetics; 20220101, Issue: Preprints p1-11, 11p
Subject
Language
ISSN
10614036; 15461718
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 ACE2expression 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, DPP9and 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.