Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis, 2023, Taylor et al

rvallee · Dec 13, 2023

We identified 73 genes linked to long COVID, of which nine genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients. Comparison of the long COVID analysis with our previous combinatorial analysis of ME/CFS patients from UK Biobank identified nine genes in common.
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Pathway enrichment analyses revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. The genes unique to Severe long COVID cohort were largely associated with immune pathways such as myeloid differentiation and macrophage foam cells while genes unique to the Fatigue Dominant cohort were enriched in metabolic pathways and processes such as MAPK/JNK signalling and cellular respiration.
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43 genes were identified to be strongly associated with the severe long COVID population who reported the greatest degree of symptoms experienced. The genes unique to the severe long COVID patients were found to be associated with immune pathways such as myeloid differentiation, macrophage foam cells and lipid signalling pathways.
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When we evaluated the degree of similarity between the genes associated with ME/CFS and long COVID, we identified nine genes that were previously associated with ME/CFS. One of these genes is the CLOCK gene that is an important regulator of circadian rhythm, disruptions of which have been associated with impaired mitochondrial function and pain among other things. Dysregulated mitochondrial function results in the inability to meet energy demands in response to stressors such as exercise and can result in the post-exertional malaise that is a hallmark of both ME/CFS and Fatigue Dominant long COVID. We also identified the genes ATP9A and INSR in long COVID that we had hypothesised contributes to dysregulated insulin signalling in subgroups of ME/CFS patients. Type 2 diabetes-related signalling pathways and insulin resistance were also a key theme within the genes associated with long COVID.When we evaluated the degree of similarity between the genes associated with ME/CFS and long COVID, we identified nine genes that were previously associated with ME/CFS. One of these genes is the CLOCK gene that is an important regulator of circadian rhythm, disruptions of which have been associated with impaired mitochondrial function and pain among other things. Dysregulated mitochondrial function results in the inability to meet energy demands in response to stressors such as exercise and can result in the post-exertional malaise that is a hallmark of both ME/CFS and Fatigue Dominant long COVID. We also identified the genes ATP9A and INSR in long COVID that we had hypothesised contributes to dysregulated insulin signalling in subgroups of ME/CFS patients. Type 2 diabetes-related signalling pathways and insulin resistance were also a key theme within the genes associated with long COVID.
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42 genes were found to be potentially tractable for novel drug discovery approaches for long COVID, of these 13 genes have drugs in clinical development pipelines. We are currently evaluating these repurposing opportunities for use in treating long COVID and/or ME/CFS.
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Trish · Dec 15, 2023

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£622,000 grant to improve diagnosis and treatment for ME/CFS and Long Covid

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Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis, 2023, Taylor et al

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Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis, 2023, Taylor et al

rvallee Senior Member (Voting Rights)

Trish Moderator Staff Member

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