Genetic Landscape of the ACE2 Coronavirus Receptor
Authors: Yang Zhijian , Macdonald-Dunlop Erin , Chen Jiantao , Zhai Ranran , Li Ting , Richmond Anne , Klarić Lucija , Pirastu Nicola , Ning Zheng , Zheng Chenqing , Wang Yipeng , Huang Tingting , He Yazhou , Guo Huiming , Ying Kejun , Gustafsson Stefan , Prins Bram , Ramisch Anna , Dermitzakis Emmanouil T. , Png Grace , Eriksson Niclas , Haessler Jeffrey , Hu Xiaowei , Zanetti Daniela , Boutin Thibaud , Hwang Shih-Jen , Wheeler Eleanor , Pietzner Maik , Raffield Laura M. , Kalnapenkis Anette , Peters James E. , Viñuela Ana , Gilly Arthur , Elmståhl Sölve , Dedoussis George , Petrie John R. , Polašek Ozren , Folkersen Lasse , Chen Yan , Yao Chen , Võsa Urmo , Pairo-Castineira Erola , Clohisey Sara , Bretherick Andrew D. , Rawlik Konrad ,   GenOMICC Consortium†,   IMI-DIRECT Consortium†, Esko Tõnu , Enroth Stefan , Johansson Åsa , Gyllensten Ulf , Langenberg Claudia , Levy Daniel , Hayward Caroline , Assimes Themistocles L. , Kooperberg Charles , Manichaikul Ani W. , Siegbahn Agneta , Wallentin Lars , Lind Lars , Zeggini Eleftheria , Schwenk Jochen M. , Butterworth Adam S. , Michaëlsson Karl , Pawitan Yudi , Joshi Peter K. , Baillie J. Kenneth , Mälarstig Anders , Reiner Alexander P. , Wilson James F. , Shen Xia 
Published: April 2022

Background:
SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.

Methods:
We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological 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 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.

Results:

We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. 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–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42];
P
=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21];
P
=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37];
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.