Familial factors in SARS-CoV-2 susceptibility and COVID-19 severity: a nationwide Danish study of adult twins and their spouses.

BACKGROUND

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often clusters in families, suggesting role of shared environmental and genetic factors. We performed a nationwide Danish study of twins, their spouses, and matched population controls with the aim of disentangling the host genetic and environmental mechanisms underlying the familial clustering of SARS-CoV-2 susceptibility and coronavirus disease 2019 (COVID-19) severity.

METHODS

This registry-linkage study included 83 902 twins and 32 719 spouses, matched to 839 020 population controls and 327 190 spouse controls, respectively, and followed from 1 February 2020 to 31 October 2022. Testing positive for SARS-CoV-2 infection and COVID-19 hospitalization served as proxies for SARS-CoV-2 susceptibility and disease severity, respectively. We compared concordance rates and calculated heritability from biometrical modelling of these traits.

RESULTS

We found no evidence of a genetic influence on infection susceptibility in the first two waves of the pandemic and a modest influence [heritability: 19.4%; 95% confidence interval (CI): 10.0%-28.8%] in the third wave. Spouses showed the highest concordance rates by a large margin in all waves. Our study found no evidence of a genetic predisposition to disease severity. Co-twins of hospitalized twins had no increased risk of hospitalization. By contrast, the risk of being hospitalized with COVID-19 was higher [relative risk: 3.56; 95% CI: 2.57-4.92] among the spouses of the hospitalized twins than among the controls.

CONCLUSION

Social proximity was a key determinant of infection susceptibility. A three-fold increased risk for spouses suggests that viral load and lifestyle shared between spouses were more important determinants of severe COVID-19 than genetic susceptibility.