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

[rvallee]

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.

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.

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.

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.

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.

 

[Trish]

A post has been moved to:
£622,000 grant to improve diagnosis and treatment for ME/CFS and Long Covid

 

[SNT Gatchaman]

See also Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements (2024, Sleep) —

The two genes that may be affected by the genotype of SNVs associated with fatigue or with actigraphic measures deserve discussion. […] rs2398428 may affect SLC15A4, which encodes solute carrier family member 15. […] rs2904106 may affect the gene ATP9A, which encodes an ATPase phospholipid transporter.

 

[forestglip]

If I understand correctly, they identified 199 SNP in the ME/CFS study of which 24 where also associated with long COVID in the Severe cohort and 27 in the Fatigue Cohort (and 12 in both the severe and fatigue cohort).

Here are those 12 SNPs that overlap between ME/CFS and both LC groups. Fully bolded SNPs were labeled as critical in both long COVID cohorts. Ones with an F or S were critical in only the fatigue or severe cohort.

ATP9A: rs6096573
ATP9A: rs77771672
GPC5: rs1536620 (F)
GPC5: rs17267214
GPC5: rs2183606
GPC5: rs6492567
INSR: rs10427021
INSR: rs6510976
INSR: rs7317941
INSR: rs8110533 (S)
PHACTR2: rs7742964
SLC15A4: rs11059915

Both of the doubly critical genes were significant in the new study linked by @SNT Gatchaman above.

 

[Hutan]

From
ATP9A deficiency causes ADHD and aberrant endosomal recycling via modulating RAB5 and RAB11 activity

Recently, ATP9A was shown to be required for the recycling pathway from the endosome to the plasma membrane and to mediate Wntless sorting, Wnt secretion and exosome release [26–28], indicating that ATP9A may be involved in cellular vesicle transport. However, the regulatory mechanism of ATP9A in mammalian endosomal transport is still unknown.

Endocytic recycling is the major pathway to maintain the abundance of receptors and transporters on the cell surface and is critical for several important cellular processes such as cell migration and cytokinesis as well as the maintenance of polarity in neurons [29]. Endocytic recycling is the process by which cargo molecules are transported from the cell surface into RAB5-positive early endosomes and recycled directly back to the plasma membrane (fast recycling) or subsequently delivered to RAB11-positive recycling endosomes, which release them outside the plasma membrane (slow recycling) [30]. Dysregulation of the expression and activity of the small GTPases RAB5 and RAB11 leads to disruption of endosomal recycling and has been linked to a variety of diseases, including cancer and central or peripheral neurological disorders [31–33].

Here, for the first time, we successfully recapitulated human neurological disease phenotypes in an ATP9A knockout mouse model and found that ATP9A deficiency causes synaptic dysfunction in primary motor cortex and hippocampus. Further studies suggest that the underlying pathogenic mechanism involves inactivation of RAB5 and RAB11. Our work highlights the critical role of ATP9A in maintaining synaptic function associated with endosome trafficking and creates a new animal model that simulates human hypotonia, ID, and ADHD disorders.

 

[SNT Gatchaman]

Endocytic recycling is the major pathway to maintain the abundance of receptors and transporters on the cell surface and is critical for several important cellular processes such as […] maintenance of polarity in neurons [29]. […] (fast recycling) or […] (slow recycling). Dysregulation […] linked to a variety of diseases, including […] central or peripheral neurological disorders.

[29] is The recycling endosome and its role in neurological disorders (2012, Progress in Neurobiology)

The recycling endosome (RE) is an organelle in the endocytic pathway where plasma membranes (proteins and lipids) internalized by endocytosis are processed back to the cell surface for reuse. Endocytic recycling is the primary way for the cell to maintain constituents of the plasma membrane (Griffiths et al., 1989), i.e., to maintain the abundance of receptors and transporters on cell surfaces. Membrane traffic through the RE is crucial for several key cellular processes including cytokinesis and cell migration. In polarized cells, including neurons, the RE is vital for the generation and maintenance of the polarity of the plasma membrane.

Hmm, that also sounds like yet another candidate explanation for FND. (Also maybe irritable bowel syndrome as gut epithelial cells are also polarised.)

 

[forestglip]

Here are those 12 SNPs that overlap between ME/CFS and both LC groups. Fully bolded SNPs were labeled as critical in both long COVID cohorts. Ones with an F or S were critical in only the fatigue or severe cohort.

ATP9A: rs6096573
ATP9A: rs77771672
GPC5: rs1536620 (F)
GPC5: rs17267214
GPC5: rs2183606
GPC5: rs6492567
INSR: rs10427021
INSR: rs6510976
INSR: rs7317941
INSR: rs8110533 (S)
PHACTR2: rs7742964
SLC15A4: rs11059915

I'm not able to edit this anymore, so adding a reply. I was looking through these SNPs, and it seems like they labeled rs7317941 incorrectly as INSR in Supplementary Table 4. dbSNP says it is part of GPC5.