Host genetic factors affecting COVID-19 disease susceptibility and severity

September 2021—More than a year into the COVID-19 pandemic, an essential question remains unanswered: Why do some people infected with SARS-CoV-2 develop severe life-threatening disease or die while others are asymptomatic or have only mild disease symptoms?

Severity of COVID-19 has been shown to be negatively affected by “typical” host factors, such as increasing age, underlying medical conditions, male gender, higher body mass index, smoking, and lower socioeconomic status.

Collectively, however, these traditional risk factors do not explain all of the variability in disease severity in the general population. Adding to the complexity of host factors, an international collaborative network of investigators, called the COVID-19 Host Genetics Initiative, has shown in a large genome-wide association study that many polymorphic loci across the human genome are highly correlated with COVID-19 disease susceptibility and severity.

To better understand the role of genetics in SARS-CoV-2 infection, the network, a consortium of approximately 3,000 researchers and clinicians, pooled clinical and genetic data from 49,562 SARS-CoV2–infected patients in 46 studies across 19 countries and six ancestry groups. Two million control subjects were accrued from a variety of sources, including biobanks, other clinical studies, and direct-to-consumer genetic companies. This large number of study participants allowed the investigators to amass sufficient statistical power to address the role of human host genetic factors in disease severity. The latter is defined categorically as infection without hospitalization, hospitalization, or critical illness requiring respiratory support or causing death. By combining this phenotypic information with detailed genotype data, the investigators identified 13 human genomic loci that were associated with SARS-CoV-2 infection susceptibility (four loci) or disease severity (nine loci). Two of the loci were discovered only after including studies of people of East Asian ancestry in the meta-analysis, highlighting the value of including diverse populations in human genetic studies.

In the genomic proximity of these 13 COVID-19 disease susceptibility loci were 40 candidate genes, many of which play a role in immune function or pulmonary pathophysiology, or both. One intriguing loci was near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases expression of the gene, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe COVID-19 included DPP9, a gene linked to lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases. Results of the meta-analysis may inform future efforts to identify those at greatest risk of severe SARS-CoV-2 infection and identify novel therapies and vaccines to ameliorate poor outcomes.

COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature. 2021.