Convergence in Pruning and Circadian Regulation in Obsessive-Compulsive Disorder and Allergic Diseases: Evidence From a Secondary Genome-Wide Analysis.

BACKGROUND

Obsessive-compulsive disorder (OCD) and allergic diseases co-occur far more often than expected, yet genome-wide genetic correlations are typically modest or negative. The objective of this study was to test whether OCD and allergic diseases show convergence at the level of pre-specified biological pathways, especially synaptic pruning and circadian regulation, rather than at the level of broad genome-wide correlation.

METHODS

Using the Multi-marker Analysis of GenoMic Annotation (MAGMA) pipeline, we re-analysed summary statistics from a large allergic-diseases genome-wide association study (GWAS) (N = 360,838). We then used gene set enrichment analysis (GSEA) and cross-tissue transcriptome-wide association study (TWAS) analyses with S-PrediXcan and Genotype-Tissue Expression (GTEx) version 8 prediction models.

RESULTS

The synaptic pruning gene set reached Bonferroni-corrected significance in allergic diseases (p = 6.75 × 10⁻⁵), driven by major histocompatibility complex (MHC) class I genes (HLA-B, HLA-A, HLA-C, TAP2), complement genes (C4A, C4B), and inflammatory regulators (NFKB1, RELA). The glutamatergic signalling set also survived the eight-set Bonferroni threshold (p = 0.005). The REACTOME Circadian Clock set showed supportive enrichment in the MAGMA analysis (raw p = 1.92 × 10⁻³; Bonferroni-adjusted p = 0.015), although this did not meet the pre-specified eight-set Bonferroni threshold of 0.0063. Standard GSEA nevertheless showed REACTOME Circadian Clock enrichment in both allergic diseases and OCD. Cross-tissue TWAS projected allergic risk onto six OCD-relevant brain regions and yielded false discovery rate (FDR)-significant pruning and circadian hits, including TAP2 in amygdala (p = 3.02 × 10⁻¹¹). Projecting OCD risk onto allergy-relevant peripheral tissues produced strong circadian gene-set enrichment, especially for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Circadian Rhythm Mammal set (1.95-fold, p = 1.62 × 10⁻⁸). Integration with published atopic dermatitis transcriptomic studies, rather than new skin transcriptomic profiling in this study, suggested global clock downregulation alongside specific shifts involving ARNTL2, NOCT, and RORC.

CONCLUSIONS

These findings support pathway-level and candidate gene-level convergence between OCD and allergic diseases, centred on pruning biology and circadian regulation. The proposed skin-brain neuroimmune loop is a hypothetical framework, not causal proof, and requires functional and longitudinal validation. The results move beyond broad polygenic correlations and identify immune-circadian pathways that may be worth testing in future mechanistic and clinical studies of comorbid patients.