Human Genomics of COVID-19 Pneumonia: Contributions of Rare and Common Variants

Abstract

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is silent or benign in most infected individuals, but causes hypoxemic COVID-19 pneumonia in about 10% of cases. We review studies of the human genetics of life-threatening COVID-19 pneumonia, focusing on both rare and common variants. Large-scale genome-wide association studies have identified more than 20 common loci robustly associated with COVID-19 pneumonia with modest effect sizes, some implicating genes expressed in the lungs or leukocytes. The most robust association, on chromosome 3, concerns a haplotype inherited from Neanderthals. Sequencing studies focusing on rare variants with a strong effect have been particularly successful, identifying inborn errors of type I interferon (IFN) immunity in 1–5% of unvaccinated patients with critical pneumonia, and their autoimmune phenocopy, autoantibodies against type I IFN, in another 15–20% of cases. Our growing understanding of the impact of human genetic variation on immunity to SARS-CoV-2 is enabling health systems to improve protection for individuals and populations. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

“…Rare and common human genetic variants have been associated with hypoxemic COVID-19 pneumonia. 1 , 2 , 3 , 4 , 5 , 6 Inborn errors of TLR3- and/or TLR7-dependent type I interferon (IFN) immunity underlie critical COVID-19 pneumonia in 1%–5% of cases. 1 , 7 , 8 , 9 Moreover, autoantibodies neutralizing type I IFN underlie at least another 15% of cases, 10 , 11 , 12 further highlighting the key role of type I IFNs in protective immunity to SARS-CoV-2 infection in the respiratory tract.…”

Lack of association between HLA and asymptomatic SARS-CoV-2 infection

“…Primary infection with SARS-CoV-2 underlies a broad spectrum of clinical manifestations in unvaccinated individuals, ranging from silent infection to lethal COVID-19 pneumonia. Rare and common human genetic variants have been associated with hypoxemic COVID-19 pneumonia [1][2][3][4][5] . Inborn errors of TLR3-and/or TLR7-dependent type I IFN immunity in respiratory epithelial cells and plasmacytoid dendritic cells underlie critical COVID-19 pneumonia in 1-5% of cases 1,[6][7][8] .…”

Human genetic determinants of COVID-19 in Brazil: challenges and future plans

“…Some of them have provided compelling evidence about the importance of genetic variants in the disease, which has helped to better understand the mechanisms of the disease. However, the impact and prevalence of rare and common variants in genes important in the COVID-19 response can change due to the genetic variability of the population studied, implying potentially different risks for each region of the globe ( Kehdy et al, 2015 ; Secolin et al, 2019 ; Zhang et al , 2022a ; Cobat et al, 2023 ).…”

“…In addition, the colonization associated with geographic and social processes also favored the formation of isolated populations groups with different genetic characteristics due to geographic isolation, endogamy, size, and effectiveness of the reduced population, being some of them have a high prevalence of genetic disorders ( Cardoso et al, 2019 ). This complex genetic pattern encompasses both common and rare variants, which can have an impact on several health conditions, including COVID-19 and other infectious diseases ( Cobat et al, 2023 ). Indeed, it has already been observed that isolated populations and private genetic variants of some populations present different impacts depending on the region and infections analyzed ( Bastard et al, 2022a ; Duncan et al, 2022 ; Couto-Silva et al, 2023 ).…”

“…Advances in technology have greatly benefited common genetic variant studies, and genome-wide association studies (GWAS) have been widely used to identify host genetic variants in the context of infectious diseases (reviewed by Kwok et al ., 2021 ). Thus, worldwide efforts have been taken during the pandemic of COVID-19 to conduct genomic investigations on common variants, resulting in the identification of several loci associated with differential outcomes of COVID-19 ( Cobat et al, 2023 ). The first and most significant locus described in GWAS associated with COVID-19 critical is 3p21.31, which encompasses six genes ( SLC6A20 , LZTFL1 , CCR9 , FYCO1 , CXCR6 , and XCR1 ) ( The Severe COVID-19 GWAS Group, 2020 ).…”