Dimensional Mapping of Post-COVID Epigenetic Ageing Biology onto MDD Symptom Profiles Suggests Distinct Pathway Modules with Implications for Precision Long COVID Care

Long COVID is frequently accompanied by fatigue, sleep disturbance, cognitive symptoms, anhedonia, psychomotor change, and depressive syndromes. Current clinical models often treat these symptoms as a single depressive phenotype, which may obscure biologically distinct post-viral pathways. We tested whether post-COVID epigenetic ageing biology maps onto specific symptom dimensions of major depressive disorder rather than onto depression as a unitary construct. We integrated a post-COVID whole-blood methylation signature derived from GSE247869, emphasizing age-associated loci including GRIN family genes, ELOVL2, PDE4C, and calcium/cAMP-related genes, with transcriptome-wide association and gene-set enrichment outputs across 12 major depression symptom dimensions from Adams et al. (2024). Ten KEGG pathways prioritized from the post-COVID ageing signature were analyzed using Stouffer meta-Z enrichment, permutation and Wilcoxon tests, bootstrap confidence intervals, family-wise false discovery rate correction, leave-one-out gene influence analysis, symptom-profile proximity metrics, opposing-pole divergence tests, and signed pathway-symptom network community detection.Fatty-acid elongation was the most pleiotropic and directionally consistent pathway, significant across 6 of 12 symptom dimensions and strongest for sleep problems, with Stouffer Z = 5.39, and death ideation, with Stouffer Z = 4.46. Opposing symptom poles showed marked biological separation: weight loss versus weight gain had a divergence index of 0.646, with all compared pathway profiles anti-correlated. Recurrent driver genes included PRKACA, CACNA1D, AKT3, ADCY genes, MAPK1, GRIN2D, GRIN1, GRIN2A, GRIA1, ELOVL2, and PDE4C. Network analysis identified four pathway-symptom communities, linking lipid/glutamatergic/calcium biology to weight, sleep, fatigue, and death-related symptoms; cAMP/MAPK/neuroactive signaling to anhedonia, worthlessness, and hypersomnia; ageing/energy pathways to depressed mood and psychomotor slowing; and synaptic vesicle biology to psychomotor activation and concentration.These findings are hypothesis-generating. They suggest that post-COVID ageing biology may perturb symptom-generating circuits through lipid elongation, glutamatergic/calcium signaling, and cAMP/PI3K-AKT hubs. The results support dimensional phenotyping, biomarker validation, and stratified Long COVID neuropsychiatry trials rather than monolithic “post-COVID depression” models.