Global and local genetic overlap among ME/CFS, irritable bowel syndrome and psychiatric traits: a hypothesis-generating analysis

Background. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and irritable bowel syndrome (IBS) frequently co-occur following infection, yet shared genetic architecture at the locus level has not been systematically characterised. Aims. To estimate global and local genetic correlations between ME/CFS (including infection-onset subgroup), IBS, major depressive disorder (MDD) and loneliness/isolation, and characterise ME/CFS cell-type heritability enrichment. Method. GWAS summary statistics: DecodeME (15,579 ME/CFS; 9,738 infection-onset), FinnGen R9 (9,296 IBS), PGC MDD Wave 2 (45,396) and UK Biobank loneliness (N=455,364). LDSC for global correlations; LAVA for local correlations across 2,495 loci; MAGMA for cell-type enrichment (Descartes Human atlas); coloc.abf for colocalisation. Results. All pairwise global correlations were significant after Bonferroni correction, including ME/CFS-all-MDD (rg=0.598, 95% CI 0.46-0.74) and ME/CFS-all-IBS (rg=0.573, 0.39-0.75). Of 4,232 local tests, 16 reached FDR<0.05; two lonelinessxMDD loci were Bonferroni-significant. ME/CFS-MDD showed three FDR-significant local correlations, but all were boundary-estimated and non-Bonferroni-significant. A borderline infection-onset ME/CFS-IBS signal occurred at chr12q24.22 ({rho}=1.000, FDR=0.046), but colocalisation did not support a shared causal variant (PP.H4=0.007). ME/CFS heritability was enriched in inhibitory neurons (P=1.210x-7) and enteric nervous system neurons (FDR=0.004), with no FDR-significant peripheral immune cell-type enrichment in the atlas used. Conclusions. High global ME/CFS-MDD correlation was accompanied by limited, boundary-estimated, non-Bonferroni-robust local sharing; the data do not support reducing ME/CFS to depression at the genetic-architecture level. Neural enrichment, including enteric nervous system neurons, supports involvement of neural components in ME/CFS susceptibility without excluding immune mechanisms. A borderline ME/CFS-IBS signal at a NOS1-containing region generated hypotheses requiring replication.