Genotype epigenome phenotype integration reveals peripheral immune contributions to type I bipolar disorder

Immune dysfunction has been increasingly implicated in bipolar disorder, but the underlying mechanisms remain unclear. To address this, we profile 833 genome-wide chromatin immunoprecipitation sequencing datasets spanning five histone marks in peripheral blood immune cells from 88 Type I bipolar disorder patients and 92 controls, integrating them with whole-genome sequencing and clinical data. We identify disease-associated cis -regulatory elements and genetically influenced regulatory elements, revealing immune signatures and pathways involving calcium signaling and endoplasmic reticulum transport. By integrating genetic risk variants, differential and genetically influenced regulatory elements, and regulatory element—gene links, we prioritize 39 driver genes, 28 of which are exclusively supported by blood evidence. We further stratify patients into five epigenomic subtypes with distinct clinical features and genetic risk profiles and identify compounds that reverse disease-associated epigenomic signatures. Here, we combine immune epigenomics with genetics and clinical traits to identify driver genes, patient subtypes, and therapeutic candidates, highlighting immune contributions to type I bipolar disorder pathogenesis.