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Source: COVID-19 Genetics  Nov 13, 2020  4 months ago
BREAKING! COVID-19 Genetics: Yale Scientist Identify Eight ‘Super’ Genetic Variants In White People That Increases COVID-19 Death Risk!
BREAKING! COVID-19 Genetics: Yale Scientist Identify Eight ‘Super’ Genetic Variants In White People That Increases COVID-19 Death Risk!
Source: COVID-19 Genetics  Nov 13, 2020  4 months ago
COVID-19 Genetics:  Scientist from Yale University in a new research have identified genetic variants among people of white British ancestry that may increase the risk of dying from COVID-19.

The study team considered 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, the team adopted the concept of super-variant for the detection of genetic factors. A discovery-validation procedure was used for verifying the potential associations.
The researchers found 8 ‘super-variants’ that contained single nucleotide polymorphisms (SNPs) located in genes that were 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.
The research findings were published on a preprint server and are currently being peer reviewed.
The study team say that the research findings may provide clues for better understanding the molecular pathogenesis of COVID-19 and the genetic basis underlying differences in susceptibility, which could potentially lead to new therapeutic options.
While the COVID-19 pandemic continues to sweep the globe, devastating public health and the economy globally, it is imperative to understand how host genetic factors are linked to clinical outcomes.
These clinical outcomes are highly heterogeneous, with many patients experiencing mild or no symptoms, while others develop severe and life-threatening symptoms.
Ever since  COVID-19 first emerged in Wuhan, China, late last year (2019), many studies have reported an increased risk of death among males and certain ethnic groups, suggesting that mortality risk at the individual level might be influenced by host genetic factors.
Although a lot of studies have been dedicated to investigating the clinical features, epidemiological characteristics of COVID-19, and genomic characterization of SARS-CoV-2, very few are through the lens of statistical genetics and the host genetic factors contributing to COVID-19 remain largely enigmatic.
In early August 2020, the UK Biobank released COVID-19 test results for 12,428 individuals. The participants included 1,778 (14.31%) infected individuals, 445 (25%) of whom died from COVID-19.
Corresponding author Dr Heping Zhang from the Department of Biostatistics, Yale University told Thailand Medical News, "This dataset accompanied by already available health care data, genetic data and death data offers a unique resource and timely opportunity for learning the host genetic determinants of COVID-19 susceptibility, severity, and mortality.”
The study team has conducted a genome-wide association study (GWAS) of the UK Biobank data on infected cases to search for genetic risk factors linked to COVID-19 mortality.
The team found that traditional single SNP GWAS was unable to detect any genome-wide significant variants, which prompted them to look for super-variants that might contribute to COVID-19 mortality.
Dr Zhang explained, "In contrast to a gene that refers to a physically connected region of a chromosome, the loci contributing to a super-variant are not restricted by its spatial location in the genome.”
The researchers identified eight super-variants as susceptibility loci for COVID-19 mortality that occurred on chromosomes 2, 6, 7, 8, 10, 16 and 17.
The study team said the most interesting signal was detected on chromosome 2 in the super-variant chr2_197, where three SNPs were identified in the gene DNAH7.
Dr Zhang said, "Gene Ontology (GO) annotations related to this gene include cilia movement and microtubule motor activity. A recently published paper showed that gene DNAH7 is the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV2."
The study team said that their findings suggest that COVID-19 patients with variations in gene DNAH7 are at an increased risk of COVID-19 mortality.
The team said, "We hypothesize that the disruption of DNAH7 gene function may result in ciliary dysmotility and weakened conciliary clearance capability, which leads to severe respiratory failure, a likely cause of COVID-19 death.”
The researchers also found that the super-variant chr16_4 on chromosome 16 is also linked to cilia.
This super-variant consists of a single SNP located in the CLUAP1 gene, which encodes clusterin-associated protein 1. This protein is required for ciliogenesis, and its GO annotations include intraciliary transport involved in cilium assembly.
The team said, "It is noteworthy that both super-variants chr2_197 and chr16_4 are related to cilia, which plays a crucial role in SARS-CoV-2 infections.”
Chr17_26 is composed by three intergenic variant SNPs. Among them, SNP rs60811869  is an eQTL of gene WSB1 in Artery-Tibial tissue based on the GTEx database. Gene WSB1 encodes a member of the WD-protein subfamily, which is highly expressed in spleen and lung. Its related pathways include innate immune system and Class I MHC mediated antigen processing and presentation. This gene has been reported to function as a Interleukin-21(IL-21) receptor binding molecule, which enhances the maturation of IL-21 receptor. Variations in this gene may result in disrupted functions of immune system and lead to higher death rate among COVID-19 patients. Super-variant chr10_57 contains 11 SNPs and all of them are located in gene PCDH15. This gene is a member of the cadherin superfamily, which encodes a Calcium-dependent cell-adhesion protein. Gene PCDH15 is essential for maintenance of normal retinal and cochlear function.
Super-variant chr8_99 is composed by 7 SNPs. All the SNPs are located in gene CPQ, which encodes carboxypeptidase Q. GO annotations of this gene include protein homodimerization activity and carboxypeptidase activity. Although the roles of genes PCDH15 and CPQ in viral infection remain largely unclear, our results warrant future investigation to learn the relationship between genetic  variations and the severe COVID-19 outcomes.
Importantly the other identified genes and SNPs located within super-variants on the other chromosomes were related to cardiovascular diseases (genes DES and SPEG), thromboembolic disease (gene STXBP5), mitochondrial dysfunctions (gene TOMM7) and the innate immune system (gene WSB1).
Dr Zhang said, "Eight genetic variants are identified to significantly increase risk of COVID-19 mortality among the patients with white British ancestry.”
The study team says that validating the identified risk factors in independent populations from other resources or ethnic groups is worth further investigation.
Significantly the study 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," concludes the study team.
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