Opposing Molecular Programs in Obsessive-Compulsive Disorder and Hoarding: Transcriptome-Wide Association Studies Reveal Distinct Senescence, Complement, and Metabolic Signatures.

BACKGROUND AND

OBJECTIVE

Obsessive-compulsive disorder (OCD) and hoarding disorder often co-occur but differ in onset, course, symptoms, and treatment response. This study compared diagnosis-based OCD genetic liability with hoarding-symptom liability, rather than direct expression differences between diagnosed patient groups.

METHODS

Large-scale OCD and hoarding genome-wide association study (GWAS) summary statistics were integrated with brain expression quantitative trait loci (eQTL) reference panels using a transcriptome-wide association approach. Gene-set enrichment was assessed across six brain regions with Stouffer's Z-score meta-analysis, empirical permutation testing, paired phenotype comparisons, and exploratory gene-level analyses. Transcriptome-wide association studies (TWAS) Z-scores were interpreted as genetically predicted expression associated with trait liability, not measured tissue expression.

RESULTS

The OCD liability showed positive intrinsic apoptosis enrichment (Z = +5.707; permutation p = 0.005899), positive complement enrichment (Z = +4.932; p = 0.0164), and a negative synapse-pruning profile (Z = -4.802; p = 0.0178). Hoarding-symptom liability showed a more positive cellular-senescence profile than OCD (Mann-Whitney U p = 0.008861; local false discovery rate (FDR) = 0.008861). Nicotinamide adenine dinucleotide (NAD)/sirtuin (SIRT) findings were directionally hoarding-skewed but exploratory.

CONCLUSIONS

These findings suggest divergent, hypothesis-generating molecular signatures, namely senescence/NAD-biased aging signals in hoarding and apoptosis, complement-pruning, and metabolic-reward dysregulation in OCD. The TWAS findings require validation with colocalization, fine-mapping, and functional studies.