biostudies-literatureHorowitz JENCATS NIH HHS382-392https://www.ebi.ac.uk/biostudies/studies/S-EPMC9005345biostudies-literatureUnknown54(4)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 tNature geneticsGenome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease.PMC9005345UL1 TR001878Siminovitch KTzoneva GGuvenek ARoberts GHLPersaud TWolf SEZhang MVerweij NMarchini JO'Keeffe SMaxwell EBaltzell ABaras AHaas MWatanabe KLeBlanc MGWidom LZhang BAkbari PRiaz MKang HMLocke AEAyer AKosmicki JAFreudenberg JJustice AERitchie MDBackman JDStahl EGelfman SNakka PLin NKessler MLeader JBHindy GCarey DJEom GHorowitz JEKnight SCKim MMighty JSirugo GPolanco TDeubler ASalerno WLotta LALi ANishtala NJones MBMcCarthy SELopez AMaxwell EKGhosh AManoochehri KBoutkov BCantor MForsythe CBalasubramanian SKapoor MYe BDonato VFernandez DFuller EDCoignet MVYadav ABai XXin JRegeneron Genetics CenterMirshahi TDamask ALocke ABovijn JMarcketta AEconomides APanea RGuturu HStaples JCPaulding CRajagopal VNunez SRana NAbecasis GRMansfield AJCoppola GJorgenson EAveritt ARand KAVerma APark DSMcCurdy SRSharma DLanche RSun DNafde MKrasheninina OHowell KChen SBackman JSun KAbecasis GLattari MTurissini DALi DKury FSPHabegger LShuldiner ARPradhan MChen EJones MOrelus MMartinez HKaralis KPadilla MSDe TUlloa RHZiyatdinov AMalhotra SRader DJGillies CChim SMRasool AMoscati AGatta GDPartha ROverton JDMitra GHawes AHong ELDobbyn LShuldiner ACantor MNGokhale SKhrimian LSchleicher TDLi AHMbatchou JO'Dushlaine CMitnaul LJSalerno WJBanerjee NKhalid SPavlopoulos EReid JGStaples JGurski LGirshick ARDi Gioia ABeechert CGu ZRodriguez-Flores JBao SSidore CSosina OBall CALiu DPraveen KMiloscio LFerreira MARfalseGenome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease.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 t2022-01-01T00:00:00Z2022 Apr2026-05-10T01:34:47.884Z2024-11-09T04:35:30.248ZS-EPMC90053453524182510.1038/s41588-021-01006-7