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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, 300 George Street, Ste 523, New Haven, CT, 06511, USA.
Insights
Genetic factors influence COVID-19 mortality risk. Eight super variants were identified, linked to cilia, cardiovascular, and immune system functions, offering new therapeutic insights.
Area of Science:
- Genetics
- Immunology
- Epidemiology
Background:
- COVID-19 severity varies significantly, with higher mortality observed in males and certain ethnic groups.
- This heterogeneity suggests a potential role for host genetic factors in determining individual risk of death from COVID-19.
Purpose of the Study:
- To investigate the genetic basis of COVID-19 mortality by performing a genome-wide association study (GWAS).
- To enhance GWAS power and detect multi-locus interactions using the super variant concept.
Main Methods:
- Genome-wide association study (GWAS) of 1778 COVID-19 cases (445 deaths) from the UK Biobank.
- Application of the super variant concept to increase the power of genetic association detection.
- A discovery-validation procedure to confirm potential genetic associations.
Main Results:
- Identified 8 super variants consistently associated with COVID-19 mortality risk across replications.
- Associated loci on chromosomes 2, 6, 7, 8, 10, 16, and 17 implicate genes in cilia dysfunction (DNAH7, CLUAP1), cardiovascular disease (DES, SPEG), thromboembolic events (STXBP5), mitochondrial function (TOMM7), and innate immunity (WSB1).
- DNAH7 was noted as significantly downregulated in SARS-CoV-2 infected bronchial cells.
Conclusions:
- Eight genetic variants significantly increase COVID-19 mortality risk in individuals of white British ancestry.
- Findings provide insights into COVID-19 molecular pathogenesis and genetic susceptibility.
- Potential implications for developing new 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 heterogeneous. 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 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails 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-CoV-2.
Conclusions:
Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.