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[Preprint]. 2021 Jun 10:2020.12.14.20248176.
doi: 10.1101/2020.12.14.20248176.

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

J E Horowitz #  1 , J A Kosmicki #  1 , A Damask #  1 , D Sharma  1 , G H L Roberts  2 , A E Justice  3 , N Banerjee  1 , M V Coignet  2 , A Yadav  1 , J B Leader  3 , A Marcketta  1 , D S Park  2 , R Lanche  1 , E Maxwell  1 , S C Knight  2 , X Bai  1 , H Guturu  2 , D Sun  1 , A Baltzell  2 , F S P Kury  1 , J D Backman  1 , A R Girshick  2 , C O'Dushlaine  1 , S R McCurdy  2 , R Partha  2 , A J Mansfield  1 , D A Turissini  2 , A H Li  1 , M Zhang  2 , J Mbatchou  1 , K Watanabe  1 , L Gurski  1 , S E McCarthy  1 , H M Kang  1 , L Dobbyn  1 , E Stahl  1 , A Verma  4 , G Sirugo  4 ; Regeneron Genetics Center; M D Ritchie  4 , M Jones  1 , S Balasubramanian  1 , K Siminovitch  1 , W J Salerno  1 , A R Shuldiner  1 , D J Rader  4 , T Mirshahi  3 , A E Locke  1 , J Marchini  1 , J D Overton  1 , D J Carey  3 , L Habegger  1 , M N Cantor  1 , K A Rand  2 , E L Hong  2 , J G Reid  1 , C A Ball  2 , A Baras  1 , G R Abecasis  1 , M A Ferreira  1
Affiliations

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

J E Horowitz et al. medRxiv. .

Update in

  • Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease.
    Horowitz JE, Kosmicki JA, Damask A, Sharma D, Roberts GHL, Justice AE, Banerjee N, Coignet MV, Yadav A, Leader JB, Marcketta A, Park DS, Lanche R, Maxwell E, Knight SC, Bai X, Guturu H, Sun D, Baltzell A, Kury FSP, Backman JD, Girshick AR, O'Dushlaine C, McCurdy SR, Partha R, Mansfield AJ, Turissini DA, Li AH, Zhang M, Mbatchou J, Watanabe K, Gurski L, McCarthy SE, Kang HM, Dobbyn L, Stahl E, Verma A, Sirugo G; Regeneron Genetics Center; Ritchie MD, Jones M, Balasubramanian S, Siminovitch K, Salerno WJ, Shuldiner AR, Rader DJ, Mirshahi T, Locke AE, Marchini J, Overton JD, Carey DJ, Habegger L, Cantor MN, Rand KA, Hong EL, Reid JG, Ball CA, Baras A, Abecasis GR, Ferreira MAR. Horowitz JE, et al. Nat Genet. 2022 Apr;54(4):382-392. doi: 10.1038/s41588-021-01006-7. Epub 2022 Mar 3. Nat Genet. 2022. PMID: 35241825 Free PMC article.

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=4.5×10-13) 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.

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Conflict of interest statement

Competing interests J.E.H., J.A.K., A.D., D.S., N.B, A.Y., A.M., R.L., E.M., X.B., D.S., F.S.P.K., J.D.B., C.O’D., A.J.M., D.A.T., A.H.L., J.M., K.W., L.G., S.E.M, H.M.K., L.D., E.S., M.J., S.B., K.S.M, W.J.S., A.R.S., A.E.L., J.M., J.O., L.H., M.N.C., J.G.R., A.B., G.R.A., and M.A.F. are current employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. G.H.L.R., M.V.C., D.S.P., S.C.K. A.Bal., A.R.G., S.R.M., R.P., M.Z., K.A.R., E.L.H., C.A.B. are current employees at AncestryDNA and may hold equity in AncestryDNA. The other authors declare no competing interests.

Figures

Figure 1.
Figure 1.. GWAS of 52,630 COVID-19 positive cases vs. 704,016 COVID-19 negative or unknown controls identifies a novel association with a rare variant near ACE2 that lowers gene expression and protects against COVID-19.
(A) Summary of association results for common (MAF>0.5%) and rare (MAF<0.5%) variants. (B) Regional association plot centered around rs190509934 near ACE2. (C) Breakdown of association results across studies included in the meta-analysis of rs190509934. (D) Association between rs190509934:C and ACE2 expression in liver measured in 2,035 individuals from the GHS study.
Figure 2.
Figure 2.. Association between a 6-SNP genetic risk score (GRS) and risk of hospitalization (A) and severe disease (B) among COVID-19 cases of European ancestry.
(A) Association between high genetic risk and hospitalization. Risk of hospitalization among cases is shown for individuals in the top GRS percentile, agnostic to the number of clinical risk factors present. The association was tested in three studies separately (AncestryDNA, UKB and GHS studies) using logistic regression, with established risk factors for COVID-19 included as covariates (see Methods for details). Results were then meta-analyzed across studies, for a combined sample size of 44,958 COVID-19 cases, including 6,138 hospitalized. N in red: number of COVID-19 cases in the top GRS percentile. Error bars represent 95% confidence intervals. (B) Association between high genetic risk and severe disease. The association was tested as described above in three studies separately (AncestryDNA, UKB and GHS studies). Results were then meta-analyzed across studies, for a combined sample size of 44,958 COVID-19 cases, including 1,940 with severe disease. N in red: number of COVID-19 cases in the top GRS percentile. N in grey: number of COVID-19 cases in the rest of population.
Figure 3.
Figure 3.. Association between a 6-SNP genetic risk score (GRS) and risk of severe disease among COVID-19 cases of European ancestry after stratifying by the presence of clinical risk factors.
(A) Rate of severe disease in the AncestryDNA study (25,353 COVID-19 cases, including 667 with severe disease). (B) Rate of severe disease in the UK Biobank study (14,320 COVID-19 cases, including 951 with severe disease). High genetic risk (red bars): top 10% of the GRS. Low genetic risk (grey bars): bottom 90% of the GRS (i.e. all other COVID-19 cases). Error bars (black) represent 95% confidence intervals.
See this image and copyright information in PMC

References

    1. Zhu N. et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine 382, 727–733 (2020). - PMC - PubMed
    1. Guan W.J. et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 382, 1708–1720 (2020). - PMC - PubMed
    1. Zhou F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). - PMC - PubMed
    1. Cummings M.J. et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet 395, 1763–1770 (2020). - PMC - PubMed
    1. Lopez L. 3rd, Hart L.H. 3rd & Katz M.H. Racial and Ethnic Health Disparities Related to COVID-19. JAMA (2021). - PubMed

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