Host genetic "super-variants" may increase COVID-19 death risk

Researchers at Yale University have identified genetic variants among people of white British ancestry that may increase the risk of dying from coronavirus disease 2019 (COVID-19) – the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The team identified eight "super-variants" that contained single nucleotide polymorphisms (SNPs) located in genes related to cilia dysfunction, cardiovascular disease, thromboembolic disease, mitochondrial dysfunctions and the innate immune system.

One SNP occurred within a gene called DNAH7, which was recently reported to be the most downregulated gene following infection of human bronchial epithelial cells with SARS-CoV-2.

The researchers say the 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.

A pre-print version of the paper is available on the server medRxiv*, while the article undergoes peer review.

"Host genetic factors contributing to COVID-19 remain largely enigmatic"

As 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 outcomes are highly heterogeneous, with many patients experiencing mild or no symptoms, while others develop severe and life-threatening symptoms.

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.

However, "while studies have been dedicated to investigating the clinical features, epidemiological characteristics of COVID-19, and genomic characterization of SARS-CoV-2, few are through the lens of statistical genetics and the host genetic factors contributing to COVID-19 remain largely enigmatic," say Heping Zhang and colleagues.

As of early August 2020, the UK Biobank has 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.

"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," say Zheng and team.

Conducting a GWAS of the UK Biobank data

Now, the 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 researchers 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.

"In contrast to a gene that refers to a physically connected region of a chromosome, the loci contributing to a super-variant is not restricted by its spatial location in the genome," explain Zheng and colleagues.

The team identified eight super-variants as susceptibility loci for COVID-19 mortality that occurred on chromosomes 2, 6, 7, 8, 10, 16 and 17.

Two super-variants related to cilia

The team says the most interesting signal was detected on chromosome 2 in the super-variant chr2_197, where three SNPs were identified in the gene DNAH7.

"Gene Ontology (GO) annotations related to this gene include cilia movement and microtubule motor activity," say the researchers. "A recently published paper showed that gene DNAH7 is the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV2."

Zheng and colleagues say their findings suggest that COVID-19 patients with variations in gene DNAH7 are at an increased risk of COVID-19 mortality.

"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," they write.

The team 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, say the researchers.

"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 infection," they write.

What about the other super-variants?

The 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).

"Eight genetic variants are identified to significantly increase risk of COVID-19 mortality among the patients with white British ancestry," writes Zheng and colleagues.

The researchers say that validating the identified risk factors in independent populations from other resources or ethnic groups is worth further investigation.

In the meantime, the findings of the current study "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 team.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.


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