Trans‐Tissue Effects of Hippocampus‐ and Blood‐Derived DNA Methylation Risk Scores on Bipolar Disorder Diagnosis

Objectives Bipolar disorder (BD) is a common psychiatric disorder with complex genetic and epigenetic underpinnings. This study aimed to investigate whether methylation risk scores (MRSs) derived from epigenome‐wide association studies (EWASs) for BD risk in living peripheral blood and postmortem hippocampal tissues are associated with BD diagnosis across tissues. Methods DNA methylation data were analyzed from two datasets, including living peripheral blood samples ( n = 40) and postmortem hippocampal tissues ( n = 63) obtained from patients with BD and unaffected controls. Two EWASs using data from blood and hippocampal samples were performed to identify differentially methylated positions (DMPs), and MRSs for BD risk in blood and hippocampal samples were calculated by aggregating methylation effects across the genome. Associations between MRSs and BD diagnosis and the potential influences of genome‐wide significant (GWS) loci related to BD and health‐related confounding factors, such as smoking, body mass index (BMI), and suicide, on these associations were assessed. Results Postmortem hippocampus‐derived MRSs for BD risk were significantly associated with BD diagnosis in blood samples ( R 2 = 0.147, p = 0.026), whereas blood‐derived MRSs for BD risk showed no significant associations in postmortem hippocampal tissue. These findings were not primarily driven by CpG sites near GWS loci or health‐related confounders. However, when focusing specifically on a restricted subset of 49 CpG sites located near GWS loci, the MRSs were significantly associated with BD diagnosis ( R 2 = 0.135, p = 0.030). Conclusions Postmortem hippocampus‐derived MRSs may capture brain‐specific epigenetic changes associated with BD pathophysiology, reflecting their diagnostic relevance in living peripheral blood. Further studies with larger sample sizes and multitissue approaches are needed to validate these findings.