Brain and Blood Biomarkers of Major Depressive Disorder

Importance: Major depressive disorder (MDD) is a debilitating neuropsychiatric disease associated with high risk of death by suicide. MDD is heterogeneous, and genome-wide association studies (GWASs) have established that MDD is polygenic, reporting thousands of small-effect variants. There is a significant epigenetic component in MDD, reflecting the role of gene-environment interactions in its pathogenesis. No biomarkers or precision-medicine based treatments exist. Understanding brain methylome and gene expression profiles at the regional and cellular level and whether brain molecular pathways alterations are reflected in blood could help identify phenotype-specific biomarkers and treatment targets for MDD. Objectives: To integrate and reanalyze findings from bulk and single-nuclei omics of MDD and to determine whether they reveal overlapping brain and blood dysregulated pathways that may inform biomarker and therapeutic targets discovery. Evidence Review: Omic studies in MDD brain and blood were reviewed using PubMed, Embase, and Web of Science. Articles were included if they used human biospecimens, reported differentially expressed or methylated genes when comparing MDD with control, and used RNA sequencing or methylation profiling. In addition, bulk and single nucleus differentially expressed genes were compared with the NHGRI-EBI GWAS Catalog of MDD-associated gene variants. Findings: In the 54 articles included (30 in brain, 20 in blood, and 4 in both), 744 differentially expressed genes were altered in the same direction in brain and blood across studies, 43 of which overlapped with GWAS-identified MDD risk loci. A total of 544 differentially methylated genes were altered in the same direction in brain and blood across studies, 34 of which overlapped with GWAS-identified MDD risk loci. Several hub genes converged on developmental, inflammatory, transcriptional, apoptotic, and mitochondrial pathways. Conclusions and Relevance: While the individual dysregulated genes are highly variable across studies and brain regions, converging pathways and hub gene functions, including those related to neurodevelopment, mitochondria, neuroinflammation, apoptosis, and transcriptional regulation emerge across studies. Cell-type specific multiomic studies involving understudied brain regions are needed to better understand the pathophysiology of MDD and identify relevant biomarkers and treatment targets.