Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

Regeneron Genetics Center; Research Program Management & Strategic Initiatives; RGC Biology; Therapeutic Area Genetics; Analytical Genomics and Data Science; Genome Informatics; Clinical Informatics; Sequencing and Lab Operations; RGC Management and Leadership Team

doi:10.1038/s41588-021-01006-7

Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

Regeneron Genetics Center, Research Program Management & Strategic Initiatives, RGC Biology, Therapeutic Area Genetics, Analytical Genomics and Data Science, Genome Informatics, Clinical Informatics, Sequencing and Lab Operations, RGC Management and Leadership Team

Research output: Contribution to journal › Article › peer-review

117 Scopus citations

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.

Original language	English
Pages (from-to)	382-392
Number of pages	11
Journal	Nature Genetics
Volume	54
Issue number	4
DOIs	https://doi.org/10.1038/s41588-021-01006-7
State	Published - Apr 2022
Externally published	Yes

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Regeneron Genetics Center, Research Program Management & Strategic Initiatives, RGC Biology, Therapeutic Area Genetics, Analytical Genomics and Data Science, Genome Informatics, Clinical Informatics, Sequencing and Lab Operations, & RGC Management and Leadership Team (2022). Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nature Genetics, 54(4), 382-392. https://doi.org/10.1038/s41588-021-01006-7

@article{dd08881ae2a84c31b6b5d90076fffb74,

title = "Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease",

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.",

author = "{Regeneron Genetics Center} and {Research Program Management & Strategic Initiatives} and {RGC Biology} and {Therapeutic Area Genetics} and {Analytical Genomics and Data Science} and {Genome Informatics} and {Clinical Informatics} and {Sequencing and Lab Operations} and {RGC Management and Leadership Team} and Horowitz, {Julie E.} and Kosmicki, {Jack A.} and Amy Damask and Deepika Sharma and Roberts, {Genevieve H.L.} and Justice, {Anne E.} and Nilanjana Banerjee and Coignet, {Marie V.} and Ashish Yadav and Leader, {Joseph B.} and Anthony Marcketta and Park, {Danny S.} and Rouel Lanche and Evan Maxwell and Knight, {Spencer C.} and Xiaodong Bai and Harendra Guturu and Dylan Sun and Asher Baltzell and Kury, {Fabricio S.P.} and Backman, {Joshua D.} and Girshick, {Ahna R.} and Colm O{\textquoteright}Dushlaine and McCurdy, {Shannon R.} and Raghavendran Partha and Mansfield, {Adam J.} and Turissini, {David A.} and Li, {Alexander H.} and Miao Zhang and Joelle Mbatchou and Kyoko Watanabe and Lauren Gurski and McCarthy, {Shane E.} and Kang, {Hyun M.} and Lee Dobbyn and Eli Stahl and Anurag Verma and Giorgio Sirugo and Nadia Rana and Nirupama Nishtala and Mitnaul, {Lyndon J.} and Jason Mighty and LeBlanc, {Michelle G.} and Jones, {Marcus B.} and Esteban Chen and Trikaldarshi Persaud and Elias Pavlopoulos and Sheilyn Nunez and Lawrence Miloscio and Hector Martinez",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022.",

year = "2022",

month = apr,

doi = "10.1038/s41588-021-01006-7",

language = "English",

volume = "54",

pages = "382--392",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

Regeneron Genetics Center, Research Program Management & Strategic Initiatives, RGC Biology, Therapeutic Area Genetics, Analytical Genomics and Data Science, Genome Informatics, Clinical Informatics, Sequencing and Lab Operations & RGC Management and Leadership Team 2022, 'Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease', Nature Genetics, vol. 54, no. 4, pp. 382-392. https://doi.org/10.1038/s41588-021-01006-7

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T1 - Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

AU - Regeneron Genetics Center

AU - Research Program Management & Strategic Initiatives

AU - RGC Biology

AU - Therapeutic Area Genetics

AU - Analytical Genomics and Data Science

AU - Genome Informatics

AU - Clinical Informatics

AU - Sequencing and Lab Operations

AU - RGC Management and Leadership Team

AU - Horowitz, Julie E.

AU - Kosmicki, Jack A.

AU - Damask, Amy

AU - Sharma, Deepika

AU - Roberts, Genevieve H.L.

AU - Justice, Anne E.

AU - Banerjee, Nilanjana

AU - Coignet, Marie V.

AU - Yadav, Ashish

AU - Leader, Joseph B.

AU - Marcketta, Anthony

AU - Park, Danny S.

AU - Lanche, Rouel

AU - Maxwell, Evan

AU - Knight, Spencer C.

AU - Bai, Xiaodong

AU - Guturu, Harendra

AU - Sun, Dylan

AU - Baltzell, Asher

AU - Kury, Fabricio S.P.

AU - Backman, Joshua D.

AU - Girshick, Ahna R.

AU - O’Dushlaine, Colm

AU - McCurdy, Shannon R.

AU - Partha, Raghavendran

AU - Mansfield, Adam J.

AU - Turissini, David A.

AU - Li, Alexander H.

AU - Zhang, Miao

AU - Mbatchou, Joelle

AU - Watanabe, Kyoko

AU - Gurski, Lauren

AU - McCarthy, Shane E.

AU - Kang, Hyun M.

AU - Dobbyn, Lee

AU - Stahl, Eli

AU - Verma, Anurag

AU - Sirugo, Giorgio

AU - Rana, Nadia

AU - Nishtala, Nirupama

AU - Mitnaul, Lyndon J.

AU - Mighty, Jason

AU - LeBlanc, Michelle G.

AU - Jones, Marcus B.

AU - Chen, Esteban

AU - Persaud, Trikaldarshi

AU - Pavlopoulos, Elias

AU - Nunez, Sheilyn

AU - Miloscio, Lawrence

AU - Martinez, Hector

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

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U2 - 10.1038/s41588-021-01006-7

DO - 10.1038/s41588-021-01006-7

M3 - Article

C2 - 35241825

AN - SCOPUS:85128488450

SN - 1061-4036

VL - 54

SP - 382

EP - 392

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Regeneron Genetics Center, Research Program Management & Strategic Initiatives, RGC Biology, Therapeutic Area Genetics, Analytical Genomics and Data Science, Genome Informatics et al. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nature Genetics. 2022 Apr;54(4):382-392. doi: 10.1038/s41588-021-01006-7

Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease

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