tetano
Editor, Senior Moderator
Nat Genet
. 2022 Mar 3.
doi: 10.1038/s41588-021-01006-7. Online ahead of print.
Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Julie E Horowitz[SUP] #[/SUP][SUP] 1 [/SUP], Jack A Kosmicki[SUP] #[/SUP][SUP] 1 [/SUP], Amy Damask[SUP] #[/SUP][SUP] 1 [/SUP], Deepika Sharma[SUP] 1 [/SUP], Genevieve H L Roberts[SUP] 2 [/SUP], Anne E Justice[SUP] 3 [/SUP], Nilanjana Banerjee[SUP] 1 [/SUP], Marie V Coignet[SUP] 2 [/SUP], Ashish Yadav[SUP] 1 [/SUP], Joseph B Leader[SUP] 3 [/SUP], Anthony Marcketta[SUP] 1 [/SUP], Danny S Park[SUP] 2 [/SUP], Rouel Lanche[SUP] 1 [/SUP], Evan Maxwell[SUP] 1 [/SUP], Spencer C Knight[SUP] 2 [/SUP], Xiaodong Bai[SUP] 1 [/SUP], Harendra Guturu[SUP] 2 [/SUP], Dylan Sun[SUP] 1 [/SUP], Asher Baltzell[SUP] 2 [/SUP], Fabricio S P Kury[SUP] 1 [/SUP], Joshua D Backman[SUP] 1 [/SUP], Ahna R Girshick[SUP] 2 [/SUP], Colm O'Dushlaine[SUP] 1 [/SUP], Shannon R McCurdy[SUP] 2 [/SUP], Raghavendran Partha[SUP] 2 [/SUP], Adam J Mansfield[SUP] 1 [/SUP], David A Turissini[SUP] 2 [/SUP], Alexander H Li[SUP] 1 [/SUP], Miao Zhang[SUP] 2 [/SUP], Joelle Mbatchou[SUP] 1 [/SUP], Kyoko Watanabe[SUP] 1 [/SUP], Lauren Gurski[SUP] 1 [/SUP], Shane E McCarthy[SUP] 1 [/SUP], Hyun M Kang[SUP] 1 [/SUP], Lee Dobbyn[SUP] 1 [/SUP], Eli Stahl[SUP] 1 [/SUP], Anurag Verma[SUP] 4 [/SUP], Giorgio Sirugo[SUP] 4 [/SUP], Regeneron Genetics Center; Marylyn D Ritchie[SUP] 4 [/SUP], Marcus Jones[SUP] 1 [/SUP], Suganthi Balasubramanian[SUP] 1 [/SUP], Katherine Siminovitch[SUP] 1 [/SUP], William J Salerno[SUP] 1 [/SUP], Alan R Shuldiner[SUP] 1 [/SUP], Daniel J Rader[SUP] 4 [/SUP], Tooraj Mirshahi[SUP] 3 [/SUP], Adam E Locke[SUP] 1 [/SUP], Jonathan Marchini[SUP] 1 [/SUP], John D Overton[SUP] 1 [/SUP], David J Carey[SUP] 3 [/SUP], Lukas Habegger[SUP] 1 [/SUP], Michael N Cantor[SUP] 1 [/SUP], Kristin A Rand[SUP] 2 [/SUP], Eurie L Hong[SUP] 2 [/SUP], Jeffrey G Reid[SUP] 1 [/SUP], Catherine A Ball[SUP] 2 [/SUP], Aris Baras[SUP] 1 [/SUP], Gonçalo R Abecasis[SUP] 1 [/SUP], Manuel A R Ferreira[SUP] 5 [/SUP]
Collaborators, Affiliations
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[SUP]-[/SUP][SUP]8[/SUP]) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10[SUP]-[/SUP][SUP]13[/SUP]), 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.
. 2022 Mar 3.
doi: 10.1038/s41588-021-01006-7. Online ahead of print.
Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease
Julie E Horowitz[SUP] #[/SUP][SUP] 1 [/SUP], Jack A Kosmicki[SUP] #[/SUP][SUP] 1 [/SUP], Amy Damask[SUP] #[/SUP][SUP] 1 [/SUP], Deepika Sharma[SUP] 1 [/SUP], Genevieve H L Roberts[SUP] 2 [/SUP], Anne E Justice[SUP] 3 [/SUP], Nilanjana Banerjee[SUP] 1 [/SUP], Marie V Coignet[SUP] 2 [/SUP], Ashish Yadav[SUP] 1 [/SUP], Joseph B Leader[SUP] 3 [/SUP], Anthony Marcketta[SUP] 1 [/SUP], Danny S Park[SUP] 2 [/SUP], Rouel Lanche[SUP] 1 [/SUP], Evan Maxwell[SUP] 1 [/SUP], Spencer C Knight[SUP] 2 [/SUP], Xiaodong Bai[SUP] 1 [/SUP], Harendra Guturu[SUP] 2 [/SUP], Dylan Sun[SUP] 1 [/SUP], Asher Baltzell[SUP] 2 [/SUP], Fabricio S P Kury[SUP] 1 [/SUP], Joshua D Backman[SUP] 1 [/SUP], Ahna R Girshick[SUP] 2 [/SUP], Colm O'Dushlaine[SUP] 1 [/SUP], Shannon R McCurdy[SUP] 2 [/SUP], Raghavendran Partha[SUP] 2 [/SUP], Adam J Mansfield[SUP] 1 [/SUP], David A Turissini[SUP] 2 [/SUP], Alexander H Li[SUP] 1 [/SUP], Miao Zhang[SUP] 2 [/SUP], Joelle Mbatchou[SUP] 1 [/SUP], Kyoko Watanabe[SUP] 1 [/SUP], Lauren Gurski[SUP] 1 [/SUP], Shane E McCarthy[SUP] 1 [/SUP], Hyun M Kang[SUP] 1 [/SUP], Lee Dobbyn[SUP] 1 [/SUP], Eli Stahl[SUP] 1 [/SUP], Anurag Verma[SUP] 4 [/SUP], Giorgio Sirugo[SUP] 4 [/SUP], Regeneron Genetics Center; Marylyn D Ritchie[SUP] 4 [/SUP], Marcus Jones[SUP] 1 [/SUP], Suganthi Balasubramanian[SUP] 1 [/SUP], Katherine Siminovitch[SUP] 1 [/SUP], William J Salerno[SUP] 1 [/SUP], Alan R Shuldiner[SUP] 1 [/SUP], Daniel J Rader[SUP] 4 [/SUP], Tooraj Mirshahi[SUP] 3 [/SUP], Adam E Locke[SUP] 1 [/SUP], Jonathan Marchini[SUP] 1 [/SUP], John D Overton[SUP] 1 [/SUP], David J Carey[SUP] 3 [/SUP], Lukas Habegger[SUP] 1 [/SUP], Michael N Cantor[SUP] 1 [/SUP], Kristin A Rand[SUP] 2 [/SUP], Eurie L Hong[SUP] 2 [/SUP], Jeffrey G Reid[SUP] 1 [/SUP], Catherine A Ball[SUP] 2 [/SUP], Aris Baras[SUP] 1 [/SUP], Gonçalo R Abecasis[SUP] 1 [/SUP], Manuel A R Ferreira[SUP] 5 [/SUP]
Collaborators, Affiliations
- PMID: 35241825
- DOI: 10.1038/s41588-021-01006-7
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[SUP]-[/SUP][SUP]8[/SUP]) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10[SUP]-[/SUP][SUP]13[/SUP]), 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.