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

Julie Horowitz ,Alexander H Li,Veera Rajagopal,Evan K Maxwell,William Salerno,Jeffrey G Reid,Sean O’Keeffe,Manuel A R Ferreira,Olukayode Sosina,John D Overton,Joshua Backman,Michelle G Leblanc,Mona Nafde,Joseph B Leader,Kathie Sun,Nirupama Nishtala,Maria Sotiropoulos Padilla,Nadia Rana,Olga Krasheninina,Erin D Fuller,Michael Cantor,Hyun Min Kang,Minhee Kim,Marcus B Jones,Giovanni Coppola,Christopher E Gillies ,Lawrence Miloscio,Carlo Sidore,Andrew Deubler,Héctor Martínez ,Kia Manoochehri,Amy Damask,Zhenhua Gu,Adam Mansfield ,Nilanjana Banerjee,Marie V Coignet,Jiwen Xin,Rouel Lanche,Jeffrey Staples,Jan Freudenberg,Suganthi Balasubramanian,Sameer Malhotra,Raghavendran Partha,Alessandro Di Gioia,Jason Mighty,Razvan Panea,Parsa Akbari,Anurag Verma,Spencer C Knight,Michael Kessler,Luca A Lotta,Eric Jorgenson,Louis Widom,Anthony Marcketta,Arden Moscati,Kristen Howell,Xiaodong Bai,Mary E Haas ,Ashish Yadav,Elias Pavlopoulos,Caitlin Forsythe,Shek Man Chim,David A Turissini,Tooraj Mirshahi,Lauren Gurski,Anne E Justice,Lee Dobbyn,Moeen Riaz,Amelia J Averitt ,Fabrício S P Kury ,Kristin A Rand,Catherine A Ball,Andrey Ziyatdinov,Jonas Bovijn,Daniel J Rader,Goncalo R Abeçasis ,Giorgio Sirugo,Max Orelus,Manasi Pradhan,Charles Paulding,Ayşegül Güvenek ,Shane Mccarthy ,Kavita Praveen,Miao Zhang,Gannie Tzoneva,Kyoko Watanabe,Tommy Polanco,Ayesha Rasool,Juan L Rodríguez-Flores ,Alexander Lopez,Deepika Sharma,Danny S Park,Adam E Locke,Sheilyn Nunez,Alicia Hawes,Ricardo H Ulloa,Giusy Della Gatta,Esteban Chen,Thomas D Schleicher,Lori Khrimian,Joelle Mbatchou,Blair Zhang,Katherine A Siminovitch ,Sahar Gelfman,Sarah Wolf ,Ariane Ayer,Christina Beechert,Shareef Khalid,Jack A Kosmicki,Boris Boutkov,David J Carey,Suying Bao,Daniel Fernandez,Bin Ye,Niek Verweij,Nan Lin,Eli A Stahl ,Dylan Sun,Michael Lattari,Valerio Donato,Gisu Eom,Colm Ó'dúshláine ,Katia Karalis,Arkopravo Ghosh,Sujit Gokhale,Jonathan Marchini,Alan R Shuldiner,Asher K Haug Baltzell ,Manav Kapoor,Marylyn D Ritchie,Aris N Economides ,Dadong Li,Priyanka Nakka,Daren Liu,Siying Chen,Genevieve H.l Roberts ,Trikaldarshi Persaud,Shannon R Mccurdy,Tanima De,Ahna R Girshick,Lyndon J Mitnaul,George Mitra,Harendra Guturu,George Hindy,Eurie L Hong,Lukas Habegger,Aris Baras

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.

Highlights

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters human host cells via angiotensin-converting enzyme 2 (ACE2)[1]
Our analysis provides independent support for several risk variants reported in previous genome-wide association study (GWAS) of COVID-199–11 (Supplementary Table 5), including those recently reported by the COVID-19 Host Genetics Initiative (HGI)[12], to which we contributed an earlier version of these data (Supplementary Table 6)
Our analysis identified a new association between a rare variant near the ACE2 gene that decreases expression of the SARS-CoV-2 receptor and COVID-19 risk

Summary

Results

GWAS of SARS-CoV-2 infection identifies ACE2 association. We performed GWAS of COVID-19 outcomes across 52,630 individuals with COVID-19 and 704,016 individuals with no record of. Of all published genetic risk factors for COVID-19, only one variant was associated with worse outcomes among infected individuals at P < 5 × 10−8 in our analysis (rs73064425 in LZTFL1) but this likely reflects low power due to the small number of patients with severe illness that were available for analysis To address this limitation, we included in the GRS five additional variants (in/near MHC, DPP9, IFNAR2, RPL24 and FOXP4) that (1) had an association with risk of infection at P < 5 × 10−8 in published GWAS or by the HGI; and (2) were associated with worse disease outcomes among infected individuals in our data (Supplementary Tables 15 and 16), albeit at the suggestive level with current sample sizes. In our analyses, age and sex were the strongest predictors of poor outcomes in indi viduals with COVID-19 and an elevated GRS enabled a modest improvement in predictions similar to that contributed by indivi dual clinical risk factors

Discussion

Methods

Code availability