Circadian Clock Genes Modulate Synaptic Pruning Vulnerability in Obsessive-Compulsive Disorder: A Multi-Method Genetic Analysis

Background: Obsessive-compulsive disorder (OCD) is a heritable neuropsychiatric condition characterized by intrusive thoughts and repetitive behaviors. Prior genetic analyses have implicated dysregulated synaptic pruning, particularly complement-microglial pathways, as a core mechanism. Emerging evidence suggests circadian disturbances may interact with this process, but integrated genetic support has been lacking. Methods: We re-analyzed summary statistics from the 2025 OCD GWAS meta-analysis (effective N = 68,099) using MAGMA for gene- and set-based association, stratified LD score regression (LDSC) for partitioned heritability, and S-PrediXcan for transcriptome-wide imputation across six cortico-striato-thalamo-cortical brain tissues. Hypothesis-driven gene sets included pruning-related pathways and circadian clock machinery. Bidirectional two-sample Mendelian randomization tested causal relationships between circadian/sleep proxies and cognitive/plasticity traits. Results: Pruning pathways remained strongly enriched, with directional signals supporting excessive synapse elimination (e.g., elevated C4A, TMEM119; reduced LYNX1). Circadian clock genes showed robust secondary enrichment across methods (MAGMA Bonferroni-corrected p = 0.0063; LDSC 1.36-fold enrichment, p = 1.97 × 10⁻⁵⁰; TWAS mean |Z| ratio = 1.22, p = 6.33 × 10⁻⁷), driven by core components (PER1, ARNTL, RORB) and epigenetic regulators (EHMT2). Bidirectional Mendelian randomization revealed strong causal effects from higher cognitive reserve (educational attainment, intelligence) toward reduced circadian disruption (p = 10⁻⁸ to 10⁻⁴), with weaker reverse signals. Conclusions: Circadian clock genes likely act as temporal modulators of pruning sensitivity in OCD, amplifying vulnerability when misaligned. This refines the pruning hypothesis by incorporating rhythmic gating, with implications for chronotherapeutic strategies in genetically susceptible individuals.