Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Julie E. Horowitz; Jack A. Kosmicki; Amy Damask; Deepika Sharma; Genevieve H. L. Roberts; Anne E. Justice; Nilanjana Banerjee; Marie V. Coignet; Ashish Yadav; Joseph B. Leader; Anthony Marcketta; Danny S. Park; Rouel Lanche; Evan K. Maxwell; Spencer C. Knight; Xiaodong Bai; Harendra Guturu; Dylan Sun; Asher K. Haug-Baltzell; Fabrício S. P. Kury; Joshua Backman; Ahna Reza Girshick; Colm T. O’Dushlaine; Shannon McCurdy; Raghavendran Partha; Adam J. Mansfield; David A. Turissini; Alexander H. Li; Miao Zhang; Joelle S. Mbatchou

doi:10.1038/s41588-021-01006-7

Genetic & Genomic MedicineNature GeneticsMar 3, 2022

Peer-reviewed journal article

Genome-wide analysis in 756,646 individuals provides first genetic evidence that ACE2 expression influences COVID-19 risk and yields genetic risk scores predictive of severe disease

Julie E. Horowitz iD, Jack A. Kosmicki iD, Amy Damask iD, Deepika Sharma iD, Genevieve H. L. Roberts iD, Anne E. Justice iD, Nilanjana Banerjee iD, Marie V. Coignet iD, Ashish Yadav, Joseph B. Leader iD, Anthony Marcketta iD, Danny S. Park iD, Rouel Lanche, Evan K. Maxwell iD, Spencer C. Knight iD, Xiaodong Bai iD, Harendra Guturu iD, Dylan Sun iD, Asher K. Haug-Baltzell, Fabrício S. P. Kury, Joshua Backman iD, Ahna Reza Girshick, Colm T. O’Dushlaine iD, Shannon McCurdy iD, Raghavendran Partha iD, , Arden Moscati iD

Abstract

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

PDF DOI