Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID- 19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, largeeffect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.


© 2021 van Blokland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. http://creativecommons.org/licenses/by/4.0/

Cite as

van Blokland, I., Lanting, P., Ori, A., Vonk, J., Warmerdam, R., Herkert, J., Boulogne, F., Claringbould, A., Lopera-Maya, E., Bartels, M., Hottenga, J., Ganna, A., Karjalainen, J., Hayward, C., Fawns-Ritchie, C., Campbell, A., Porteous, D., Cirulli, E., Barrett, K., Riffle, S., Bolze, A., White, S., Tanudjaja, F., Wang, X., Ramirez, J., Lim, Y., Lu, J., Washington, N., de Geus, E., Deelen, P., Boezen, H. & Franke, L. 2021, 'Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility', PLoS ONE, 16(8), article no: e0255402. https://doi.org/10.1371/journal.pone.0255402

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Last updated: 16 June 2022
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