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Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data
Jianchang Hu1, Cai Li1, Shiying Wang1
1Department of Biostatistics, Yale University.
Insights
Genetic factors influence COVID-19 mortality risk. This study identified eight super-variants linked to increased death risk in patients with COVID-19, offering insights into disease susceptibility.
Area of Science:
- Genetics
- Infectious Diseases
- Genomics
Background:
- Coronavirus disease 2019 (COVID-19) severity varies significantly among individuals.
- Host genetic factors may influence the risk of death from COVID-19, particularly in certain ethnic groups.
Approach:
- A genome-wide association study (GWAS) was conducted on 1,778 COVID-19 cases from the UK Biobank, focusing on mortality.
- To improve detection power and account for gene interactions, a super-variant approach was employed, followed by a discovery-validation procedure.
Key Points:
- Eight super-variants were consistently identified as susceptibility loci for COVID-19 mortality.
- These loci are associated with genes involved in cilia dysfunction (DNAH7, CLUAP1), cardiovascular disease (DES, SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunction (TOMM7), and innate immunity (WSB1).
- DNAH7 was noted as downregulated in human bronchial epithelial cells infected with SARS-CoV-2.
Conclusions:
- Eight genetic variants significantly increase COVID-19 mortality risk in individuals of white British ancestry.
- These findings contribute to understanding COVID-19's molecular pathogenesis and the genetic basis of varied susceptibility.
- The results may inform the development of novel therapeutic strategies.
Background:
The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogenous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors.
Methods:
In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1,778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS failed to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super-variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations.
Results:
We find 8 super-variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on Chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV2.
Conclusions:
Eight genetic variants are identified to significantly increase risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely evidence and clues for better understanding the molecular pathogenesis of COVID-19 and genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.