Endocannabinoid Signaling Emerges as a Major Polygenic Contributor to Bipolar Disorder Heritability

Background: Bipolar disorder (BD) is a highly heritable condition characterized by episodic mood instability, preserved premorbid cognition, and progressive features in some patients. Recent large-scale GWAS have implicated synaptic pruning and calcium signaling, yet gaps remain in understanding cognitive reserve's paradoxical risk-amplification and potential therapeutic targets. Methods: We analyzed summary statistics from the largest European-ancestry BD GWAS (N > 150,000 cases) using MAGMA for gene-based and competitive gene-set testing, partitioned LD score regression for heritability enrichment, S-PrediXcan for transcriptome-wide associations across six brain tissues, and bidirectional two-sample Mendelian randomization. Eight hypothesis-driven gene sets were tested, including a novel overlap-removed cannabis-related set encompassing endocannabinoid synthesis, degradation, transport, and downstream pathways. Results: Glutamatergic and pruning-related sets replicated significant enrichment. Unexpectedly, the cannabis-related set—despite null aggregate signals in MAGMA and TWAS—captured the strongest partitioned heritability (1.22-fold enrichment, LD-adjusted 1.02-fold, Bonferroni-corrected p = 3.11 × 10⁻⁶⁹), independent of other pathways. Nominal associations highlighted DAGLA and SLC27A5, with TWAS replication in frontal regions. MR revealed unidirectional protection from high cognitive reserve against cannabis dependence but no robust causality with BD. Conclusions: These findings identify polygenic endocannabinoid hypofunction as a major, previously underappreciated contributor to BD liability—likely regulatory/developmental rather than transcriptional. This refines triadic models by positioning ECS deficiency as a moderator transforming reserve from protective (general population) to destabilizing (BD pruning-dominant circuits). The profile suggests selective therapeutic potential for non-intoxicating cannabinoids (e.g., CBD) in high-reserve subgroups, warranting stratified trials.