Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19), a respiratory illness with flu-like symptoms that can range from mild to severe fever, cough, and headaches. COVID-19 can cause massive immune responses, respiratory failure, hospitalization, and even death in some people. The known risk factors for COVID-19 are older age, male sex, ancestry, cardiovascular and kidney disease, obesity, and chronic obstructive pulmonary disease.
As of today, SARS-CoV-2 infection has been reported in more than 48 million individuals and has claimed 1.23 million lives worldwide. Understanding genetic variations among infected individuals could help identify mechanisms influencing the severity of disease and clinical outcomes. This information can help identify at-risk individuals and provide preventive vaccination or treatments.
Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants
A team of researchers from the Regeneron Genetics Center, NY, USA; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, UK; Biogen, Cambridge, MA, USA; Alnylam Pharmaceuticals, Cambridge, MA, USA; and Bristol Myers Squibb, Princeton, NJ recently investigated the genetic determinants of COVID-19 risk and severity in humans. Their study is published on the preprint server medRxiv*.
The study cohort included 455,838 participants of a UK Biobank study that took place between 2006 and 2010. The participants were adults in the age range of 40 to 69 and comprised 2003 patients with COVID-19. The UK Biobank provided updates on the participants' COVID-19 status, including data related to 4 main data types used in the study, namely, SARS-CoV-2 PCR test results, electronic health records, primary care data, and death registry data.
The team defined 8 COVID-19-related phenotypes for genetic association analyses. These include risks of infection, severe disease, and hospitalization, and they were tested for association with imputed and exome sequencing variants. The results reported in this study is based on September 2020 data.
What did the study find?
The researchers replicated prior genetic associations of COVID-19 with common variants in the 3p21.31 and 9q34.2 loci. The 3p21.31 locus was associated with severe disease in COVID-19 cases, but SARS-CoV-2 infection risk without hospitalization. They identified two loci associated with infection risk at
P < 5x10-8, which included a missense variant.
The association of COVID-19 with rs429358 was attenuated post adjusting for Alzheimer's and cardiovascular disease status (P = 0.005). Rare coding variant analyses found no significant associations either exome-wide or with 1) 14 genes linked to interferon signaling that were reported to have rare deleterious variants in COVID-19 patients with severe disease; 2) 36 genes located in the 3p21.31 and 9q34.2 GWAS risk loci, and 3) 31 genes of immunologic relevance or treatment potential.
The study also found associations between increased SLC6A20 expression in the GI tract, kidney, or lung and increased viral uptake, leading to severe disease.
"One intriguing hypothesis is that increased expression of SLC6A20 in the gastrointestinal tract, lung or kidney might promote viral uptake, thus leading to increased risk of severe disease due to pathology in these tissues."
Older, non-European males at higher risk of COVID-19 hospitalizations and deaths
Based on the results of their analyses, the authors concluded that older males of non-European ancestry are more prone to severe COVID-19, hospitalizations, and deaths.
"Our analysis of COVID-19 in the UK Biobank indicates that consistent with observational 351 studies in the same UK participants, COVID-19-related hospitalizations and deaths skew towards older, male individuals of non-European ancestry."
The analyses performed in this study corroborates the association of COVID-19 with the 3p21.31 locus. It also shows that no rare protein-coding variant associations with effect sizes are detectable at these sample sizes. The results of the full analysis are available publicly at https://rgc-covid19.regeneron.com and this provides a substrate for meta-analysis when results from other sequenced COVID-19 cases become available.
A better understanding of host mechanisms that offer protection from SARS-CoV-2 infection or that influence disease severity might help guide the development of vaccines or drugs to fight SARS-COV-2.
"Further genetic studies across ancestry groups will shed more light on human genetic risk factors associated with susceptibility to SARS-CoV-2 and may point to pathways and approaches for the treatment of COVID-19."
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants J. A. Kosmicki, J. E. Horowitz, N. Banerjee, R. Lanche, A. Marcketta, E. Maxwell, Xiaodong Bai, D. Sun, J. Backman, D. Sharma, C. O'Dushlaine, A. Yadav, A. J. Mansfield, A. Li, J. Mbatchou, K. Watanabe, L. Gurski, S. McCarthy, A. Locke, S. Khalid, O. Chazara, Y. Huang, E. Kvikstad, A. Nadkar, A. O'Neill, P. Nioi, M. M. Parker, S. Petrovski, H. Runz, J. D. Szustakowski, Q. Wang, Regeneron Genetics Center, UKB Exome Sequencing Consortium, M. Jones, S. Balasubramanian, W. Salerno, A. Shuldiner, J. Marchini, J. Overton, L. Habegger, M. N. Cantor, J. Reid, A. Baras, G. R. Abecasis, M. A. Ferreira medRxiv 2020.10.28.20221804; doi: https://doi.org/10.1101/2020.10.28.20221804, https://www.medrxiv.org/content/10.1101/2020.10.28.20221804v1