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

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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 ^{# 1} , Jack A Kosmicki ^{# 1} , Amy Damask ^{# 1} , Deepika Sharma ¹ , Genevieve H L Roberts ² , Anne E Justice ³ , Nilanjana Banerjee ¹ , Marie V Coignet ² , Ashish Yadav ¹ , Joseph B Leader ³ , Anthony Marcketta ¹ , Danny S Park ² , Rouel Lanche ¹ , Evan Maxwell ¹ , Spencer C Knight ² , Xiaodong Bai ¹ , Harendra Guturu ² , Dylan Sun ¹ , Asher Baltzell ² , Fabricio S P Kury ¹ , Joshua D Backman ¹ , Ahna R Girshick ² , Colm O'Dushlaine ¹ , Shannon R McCurdy ² , Raghavendran Partha ² , Adam J Mansfield ¹ , David A Turissini ² , Alexander H Li ¹ , Miao Zhang ² , Joelle Mbatchou ¹ , Kyoko Watanabe ¹ , Lauren Gurski ¹ , Shane E McCarthy ¹ , Hyun M Kang ¹ , Lee Dobbyn ¹ , Eli Stahl ¹ , Anurag Verma ⁴ , Giorgio Sirugo ⁴ , Regeneron Genetics Center; Marylyn D Ritchie ⁴ , Marcus Jones ¹ , Suganthi Balasubramanian ¹ , Katherine Siminovitch ¹ , William J Salerno ¹ , Alan R Shuldiner ¹ , Daniel J Rader ⁴ , Tooraj Mirshahi ³ , Adam E Locke ¹ , Jonathan Marchini ¹ , John D Overton ¹ , David J Carey ³ , Lukas Habegger ¹ , Michael N Cantor ¹ , Kristin A Rand ² , Eurie L Hong ² , Jeffrey G Reid ¹ , Catherine A Ball ² , Aris Baras ¹ , Gonçalo R Abecasis ¹ , Manuel A R Ferreira ⁵



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^-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.