Genetic mechanisms of critical illness in Covid-19

Abstract

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs[PMID: 32526193] and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.[PMID: 32678530] Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.[PMID: 24855243] GenOMICC (Genetics Of Mortality In Critical Care, <a href="https://genomicc.org">genomicc.org</a>) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p = 1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30).

Host genetics and infectious disease: new tools, insights and translational opportunities

“…156 ). The limitations of self-reported data notwithstanding, a large GWAS of more than 1.05 million individuals from the 23andMe research platform replicated the associations at these two loci for disease severity 157 , while the GenOMICC investigators recruited patients with COVID-19 from intensive care units only and robustly reproduced the 3p21.31 signal in addition to finding associations at other loci, including ones with genes of well-known antiviral function such as 12q24.13 (OAS1, OAS2 and OAS3) and 21q22.1 (IFNAR2) 158 .…”

“…The importance of type I interferons in protective immunity against SARS-CoV-2 was underlined by an accompanying article showing evidence for a high level of neutralizing autoantibodies to type I interferons in other patients with critical COVID-19, together highlighting the opportunities for therapeutic intervention based on screening at-risk individuals and developing targeted interventions 163 . Indeed, in the GenOMICC study described above, beyond uncovering key potential genetic contributions to COVID-19 severity, the group further used Mendelian randomization to demonstrate a link between low IFNAR2 expression and high TYK2 expression and life-threatening disease, the former further evidencing the importance of type I interferons in COVID-19 pathogenesis 158 . Altogether, the emerging insights from this fast-moving field of research exemplify the complex nature of the genetic architecture of susceptibility to infectious disease that may have relevance not only for the agent inflicting the largest pandemic of our generation but also potentially for a range of other infections afflicting our public health worldwide.…”

A genetic variant protective against severe COVID-19 is inherited from Neandertals

“…The index variants for the three novel loci (rs10735079, rs2109069, rs2236757) were obtained from GenOMICC (Pairo-Castineira et al 2020). The regional summary statistics from the round 4 (alpha) release of the meta-analysis carried out by the COVID-19 Host Genetics Initiative (https://covid19hg.org/results) was used to analyze the chromosome 12 locus.…”

“…A new study from the GenOMICC consortium, which includes 2,244 critically ill COVID-19 patients and controls (Pairo-Castineira et al . 2020), identifies three new loci with genome-wide significant effects in addition to the risk locus on chromosome 3 located on chromosomes 12, 19 and 21.…”

Immunogenetic Association Underlying Severe COVID-19

“…One GWAS assay using two case-control European panels associated severe-COVID-19 with locus Chr9q34.2, which concurs the ABO blood group locus [22]. However, this association was not significantly demonstrated in two other GWAS assays published [23,24], indicating that the association of blood type locus with severe COVID-19 is not as universal as the chemokine receptor locus at Chr3p21.31 (Table 1). Therefore, more studies are needed to extensively verify the association of blood types with the progression of COVID-19 severity.…”