Gene-Level Convergence in Pruning and Circadian Regulation Underpins OCD–Allergy Comorbidity

Obsessive-compulsive disorder (OCD) and allergic diseases co-occur far more often than expected by chance (adjusted odds ratios 1.6–2.4), yet genome-wide genetic correlations between the traits are typically modest or negative. This study resolves that apparent paradox by demonstrating robust convergence at the pathway level. Using the identical MAGMA pipeline applied to the 2025 OCD GWAS, we re-analyzed summary statistics from a large allergic-diseases GWAS (N = 360,838) [1]. The curated synaptic pruning gene set reached Bonferroni-corrected significance (p = 6.75 × 10⁻⁵), driven by MHC Class I (HLA-B, HLA-A, HLA-C, TAP2), complement (C4A, C4B), and inflammatory regulators (NFKB1, RELA). The REACTOME circadian clock set was independently enriched (p = 0.015), with PSMD3 as the leading gene. Negative-control sets (housekeeping, monoamines) showed no enrichment, confirming specificity.Cross-tissue transcriptome-wide association studies (S-PrediXcan, GTEx v8) closed the mechanistic loop. Projecting allergic risk onto six OCD-relevant brain regions yielded multiple FDR-significant pruning and circadian hits (e.g., TAP2 p = 3.02 × 10⁻¹¹ in amygdala) [2]. Conversely, projecting OCD risk onto skin and allergy-relevant tissues produced extreme circadian enrichment (KEGG core clock set: 1.95-fold, p = 1.62 × 10⁻⁸). Integration with atopic dermatitis skin transcriptomics revealed global clock downregulation alongside specific shifts (ARNTL2 and NOCT upregulated; RORC downregulated), impairing nocturnal barrier repair and amplifying Th2 inflammation [3,4].These findings support a unified gene-level model in which shared MHC/complement-microglial-oligodendroglial pruning variants are temporally gated by circadian clock genes and amplified by peripheral Th2-driven skin clock disruption, generating a self-reinforcing skin–brain neuroimmune loop. The work moves beyond broad polygenic correlations to identify actionable pathways and suggests that integrated immune-circadian interventions may improve outcomes in comorbid patients.