Major depressive disorder (MDD) is a complex and heterogeneous psychiatric syndrome with genetic and environmental influences. In addition to neuroanatomical and circuitous abnormalities, dysregulation of the brain transcriptome is a key phenotypic feature of MDD.

Molecularly, depression is a multigenic syndrome. The morbid pathology results from a very large number of small changes that occur in the genome and affect the expression of hundreds of genes, and these processes are strongly influenced by adverse experiences throughout life. Thus, the onset of depression at the transcriptomic level is thought to result from an accumulation of genetic risk and molecular responses to environmental exposures that converge in specific functional gene networks, resulting in persistent dysregulation of the entire transcriptome.

The impact of genetic predisposition to MDD on cellular phenotypes and their development can be captured using human induced pluripotent stem cell (hiPSC) techniques, which preserve the donor genetic background in a wide variety of MDD-associated cell types. Moreover, hiPSC-derived neurons are thought to most closely resemble their fetal counterparts. Consequently, the transcriptional differences observed in hiPSC-derived cells only characterise the effects of donor genetic risk and cannot explain those risk factors for depression that are not heritable. It is suggested that conservation of epigenetic markers can be achieved by direct reprogramming strategies if donor-specific epigenetic profiles, such as those in aging, are of interest. Being experimentally powerful, hiPSC models cannot yet reliably simulate interactions between cells and contours of the intact brain, although innovations in organoid tissue culturing techniques are closing this gap.

Peripheral tissues, such as blood plasma, are a non-invasive surrogate source of transcriptomic data in living patients with IBD that can be used to identify clinical biomarkers. Blood gene expression is assumed to be largely unrepresentative of brain gene expression, with correlations between tissue levels of gene expression ranging from 0.25 to 0.64. Thus, blood transcriptomes are less likely to provide etiological insight into the biology of depression while the brain is considered the primary source of pathology. However, mechanisms of brain-immune interactions suggest that expression of peripheral immune genes bi-directionally affects brain transcription and may contribute to neuropsychopathology. As researchers determine the dynamics of transcription between blood and brain, blood transcription profiles remain most useful as a surrogate for biomarkers of depression and response to treatment.