Blood-Based Precision Epigenomics for Elucidating the Molecular Basis of Psychiatric Disorders

Abstract

This dissertation demonstrates that blood-based DNA methylation changes provide crucial insights into the biological mechanisms underlying psychiatric disorders and represent an initial step toward defining the personal epigenome. Given the global increase in psychiatric disorders, elucidating their molecular basis is of growing importance. To understand and discover predictive biomarkers of mental diseases, we identified and validated methylation biomarkers associated with anxiety and suicide attempt in Koreans. In anxiety disorders, validated epibiomarkers implicated pathways involved in neurosignaling, synaptic regulation, apoptosis, and mitochondrial dysfunction. In suicide attempts, epibiomarkers primarily linked to synaptic signaling were consistently detected in both blood and postmortem brain tissues, indicating cross-tissue and cross-ethnic relevance. To address the limitations of GRCh38 in epigenomic analyses, we identified CpG-creating variants specific to the Korean population using the Korea10K Genome Project, which revealed an increased number of CG sites near genes associated with psychiatric disorders in Koreans. Additionally, suicide-associated epibiomarkers were discovered from novel CpG sites created by DNA variants, emphasizing the significance of ethnicity-informed epigenetic variation. Collectively, these findings suggest that psychiatric disorders exhibit systemic epigenetic signatures detectable in blood, providing a basis for personalized and precision mental health diagnostics.