Table 3.
Genes and communities identified in the Pain Questionnaire cohort and their proposed mechanism of action (MoA) in ME/CFS development (accounting for eQTL directionality)
| Gene | Community | MoA category | MoA evidence |
|---|---|---|---|
| S100PBP | 1 | Viral/bacterial susceptibility | Identified as a differentially expressed gene (DEG) in response to RSV infection [42] |
| ATP9A | 1 | Metabolic | Exhibits P4-ATPase activity in beta cells and ATP9A knockdown results in reduction in glucose-stimulated insulin release [43] |
| Autoimmune | Splicing region in ATP9A associated with multiple sclerosis risk in whole-exome sequencing analysis [44] | ||
| KCNB1 | 1 | Metabolic | Regulates insulin exocytosis from pancreatic beta cells [45] |
| CLOCK | 2 | Sleep | Key regulator of circadian rhythm [46] |
| Metabolic | Disruption to circadian clock results in mitochondrial dysfunction and insulin resistance [47, 48] | ||
| SLC15A4 | 3 | Autoimmune | SLC15A4 mediates type 1 interferon production and generation of autoantibodies in systemic lupus erythematosus (SLE) [49] |
| Metabolic | Knock down of SLC15A4 decreases mitochondrial membrane potential and impairs AMPK activation [50, 51] | ||
| TMEM232 | 6 | Autoimmune | The promoter region of TMEM232 is differentially methylated in a study of multiple sclerosis patients [52] |
| GPC5 | 7 | Autoimmune | Polymorphisms in GPC5 have been associated with multiple sclerosis risk in GWAS [53, 54] |
| PHACTR2 | 8 | Autoimmune | Identified as a multiple sclerosis risk gene in a GWA analysis [55] |
| AKAP1 | 9 | Metabolic | AKAP1 is an AMPK substrate that regulates mitochondrial respiration [56] |
| Viral/bacterial susceptibility | AKAP1-/- mice exhibit increased inflammation and immune cell infiltration in lungs [57] | ||
| USP6NL | 12 | Viral/bacterial susceptibility | Plays a role in HSV-1 virion assembly [58] |
| CDON | 13 | Metabolic | Cdon depletion results in impaired muscle regeneration and increased cell stress [59] |
| Autoimmune | Cdon is involved in differentiation and myelination of oligodendrocytes [60] | ||
| Viral/bacterial susceptibility | GWAS indicates CDON plays a role in complicated Staphylococcus aureus bacteremia [61] | ||
| INSR | 14 | Metabolic | Receptor tyrosine kinase which mediates insulin signalling [62] |
| SULF2 | 15 | Viral/bacterial susceptibility | Genome-wide environmental interaction study indicates an association between a locus in SULF2 and HSV-1 seropositivity and depression [63] |
| Metabolic | Overexpression of SULF2 observed in subjects with type 2 diabetes and obesity [64] | ||
| SLC6A11 | 15 | Sleep | Associated with depression, sleep disturbance and neuropathic pain in mouse models [65, 66] |
| Autoimmune | Expression decreased in the hippocampus of mouse model of multiple sclerosis (EAE) [67] |