ABSTRACT: Immune dysfunction is increasingly implicated in bipolar disorder (BD), yet its mechanistic basis remains unclear. To address this, we profile and integrate 833 genome-wide ChIP-seq datasets of five histone modifications from peripheral blood immune cells of 180 individuals (88 type I BD patients, 92 controls), with whole-genome sequencing data and clinical records. We annotate 450k candidate cis-regulatory elements (CREs) based on ChIP-seq peaks and identify BD-associated differential CREs (dCREs), revealing down-regulated adaptive and up-regulated innate immune response signatures. We next map histone quantitative trait loci (QTLs) and identify genetically driven CREs (gCREs) associated with BD genetic variants, which linked to genes involved in calcium signaling and endoplasmic reticulum transport, pathways essential in both immune and neuronal function. Integrating dCREs, gCREs, and CRE-gene links, we prioritize 39 candidate driver genes in circulating immune cells, including ORMDL3, a pivotal gene associated with inflammation in asthma and ulcerative colitis. Most of these genes are associated with BD variants via blood-specific eQTLs absent in brain cells, suggesting peripheral immune-specific regulatory mechanisms. We further stratify BD patients into five epigenomic subtypes with distinct clinical features, including inflammation, glucose intolerance, and hypertension. Immune-partitioned polygenic risk scores predict these subtypes, supporting a genetic basis for immuno-epigenomic heterogeneity. Finally, we identify hundreds of drugs/compounds whose perturbation signatures counter BD-associated immune dysfunction, including drugs with known effects on the nervous system, cancers, and the cardiovascular system, offering repurposing opportunities tailored to BD patients based on inflammatory signatures. Our findings reveal a potential causal role for circulating immune cells in BD and highlight how our integrative approaches can uncover immune mechanisms and empower precision medicine in complex, non-canonical immune diseases, such as BD.
