Genotype-Epigenome-Phenotype Integration Reveals the Contributions of Peripheral Immune Cells to Bipolar Disorder Pathogenesis, Phenotypic Heterogeneity, and Therapy

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.