Newswise — Researchers have discovered a mechanism for susceptibility to COVID-19 using a newly created tool. The tool, GASPACHO, captures dynamic changes in gene expression along the innate immune response, enabling researchers to identify genes and molecular pathways associated with disease risk that were previously too complex to detect or interpret.

Using GASPACHO (GAuSsian Processes for Association mapping leverageing Cell HeterOgeneity), researchers from the Wellcome Sanger Institute, National Center for Child Health and Development in Japan, Tel Aviv University and their collaborators identified a genetic variant that affects susceptibility to COVID-19. Understanding the genetic factors that contribute to COVID-19 infection and severity may provide new biological insights into the pathogenesis of the disease and identify therapeutic targets. It is hoped that the tool can be applied to uncover additional susceptibility mechanisms in other human disorders.

The study, published in Genetics of nature (June 12), helps unravel the relationship between specific genes, their expression levels, and their potential connection in disease susceptibility. The team highlights the usefulness of the tool with a COVID-19 case study.

There is wide variation in how people respond to COVID-19. About 80% of those infected experience a mild to moderate attack of the disease, while some will experience mainly respiratory symptoms that are much more severe, requiring hospitalization and even intensive care. Some of this variation may be due to differences in our genes, especially differences in our genetic regulation of gene expression.

The regions that affect gene expression are called quantitative expression trait loci (eQTL). These are like markers in our DNA that indicate which genetic variations are linked to changes in the expression of certain genes, affecting how much or how little a gene is compounded up or down, leading to differences in protein levels​ produced by that gene.

While genome-wide association studies (GWAS) have identified numerous disease-associated variants involved in gene expression, implicating the involvement of eQTLs, they are unable to show any causal relationship. Genome-wide eQTL mapping, however, has shown the potential to reveal underlying genetic mechanisms of variation in disease outcomes.

In the new study, the scientists set out to explore patient-specific immune responses by mapping eQTLs. They employed a novel approach to show how genetic variation within cells affects the overall immune response between individuals.

Researchers at the Wellcome Sanger Institute and their collaborators in Japan and Tel Aviv University triggered an antiviral response in human fibroblast cells from 68 healthy donors, then profiled them using single-cell transcriptomics to challenge GASPACHO.

The tool uses non-linear regression modeling* to capture dynamic changes in eQTLs that occur at different stages of the immune response. Unlike previous eQTL mapping efforts that aggregate single cell data, measuring average gene expression across many cells, GASPACHO enables cell-specific resolution to track changes over time and between individual cells.

The team identified 1,275 eQTLs within the genome that alter gene expression along the innate immune response among people, relevant to 40 immune-related diseases such as Crohn’s disease and diabetes.

The researchers found that when applying the tool to study variation in COVID-19 outcomes, the lower expression of OSA1 the genetic variation occurred in those most likely to get COVID-19. THE OSA1 gene encodes a protein involved in the elimination of viral RNA from the cell.

In COVID-19 patients, the team found lower values OSA1 expression in nasal epithelial cells and blood monocytes – both viral target cell types – compared to a reference genotypic group. Their findings suggest so OSA1 the expression can be modulated by a common splicing variant, OSA1 QTL splicing, to these target cell types. This is a genetic alteration in the DNA sequence at the boundary between an exon and an intron. In these cells, the splicing variant will likely directly affect the efficacy of viral RNA clearance in the individual, explaining the compromised clinical outcome in the COVID-19 patient group.

While this genetic alteration needs to be further explored to fully understand the role it plays, it offers insights into the molecular mechanisms underlying susceptibility to COVID-19 and other immune-related diseases, providing a basis for the development of potential therapies that exploit these mechanisms. genetics.

Dr Natsuhiko Kumasaka, first author of the study from the National Center for Child Health and Development in Japan, said: ‘In the future we may be able to use OSA1 and other genes on the same cascade in drug discovery or as therapeutic targets, but more research is needed to understand the specific mechanisms by which OSA1 or related genes may contribute to COVID-19.

Dr Tzachi Hagai, co-lead author of the study from Tel Aviv University, said: ‘It is remarkable how small differences in our genetic makeup can affect our health and susceptibility to disease, simply by influencing the activity of our genes. . While host-specific genetic factors are only part of the puzzle, our work sheds light on the molecular mechanisms underlying various traits, diseases and drug responses, and how these may interact across broader environmental, clinical and social factors. The findings here underscore the importance of ongoing scientific investigations to unravel the complex interactions between human genetics and the outcome of infection with pathogens, including by emerging viruses such as SARS-CoV-2.

Dr Sarah Teichmann, co-lead author of the study from the Wellcome Sanger Institute and co-chair of the Human Cell Atlas organizing committee**, said: ‘This new tool will be important in extracting meaningful insights from the massive amount of data which is generating the Human Cell Atlas, in its aim to map every cell type in the human body.Using the tool, we hope to uncover many underlying genetic mechanisms and ultimately drug targets to aid in the development of new treatments for a variety of diseases”.


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