Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood.
Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic correlates of circulating ACE2. Using the summary-statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.
Results: We identified ten loci, including eight novel, capturing 30% of the protein's heritability. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 0.02). Tissue- and cell-type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.
Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
Yang, Z., MacDonald-Dunlop, E., Chen, J., Zhai, R., Li, T., Richmond, A., Klaric, L., Pirastu, N., Ning, Z., Zheng, C., Wang, Y., Huang, T., He, Y., Guo, H., Ying, K., Gustafsson, S., Prins, B., Ramisch, A., Dermitzakis, E., Png, G., Eriksson, N., Haessler, J., Hu, X., Zanetti, D., Boutin, T., Hwang, S., Wheeler, E., Pietzner, M., Raffield, L., Kalnapenkis, A., Peters, J., Viñuela, A., Gilly, A., Elmståhl, S., Dedoussis, G., Petrie, J., Polašek, O., Folkersen, L., Chen, Y., Yao, C., Võsa, U., Pairo-Castineira, E., Clohisey, S., Bretherick, A., Rawlik, K., Esko, T., Enroth, S., Johansson, Å., Gyllensten, U., Langenberg, C., Levy, D., Hayward, C., Assimes, T., Kooperberg, C., Manichaikul, A., Siegbahn, A., Wallentin, L., Lind, L., Zeggini, E., Schwenk, J., Butterworth, A., Michaëlsson, K., Pawitan, Y., Joshi, P., Baillie, J., Mälarstig, A., Reiner, A., Wilson, J. & Shen, X. 2022, 'Genetic landscape of the ACE2 coronavirus receptor', Circulation. https://doi.org/10.1161/CIRCULATIONAHA.121.057888