Analysis of Genomic and Transcriptomic Data Revealed Key Genes and Processes in the Development of Major Depressive Disorder

Major depressive disorder (MDD) is one of the most common diseases, affecting millions of people worldwide. Existing antidepressants do not allow sustainable remission to be achieved in many cases, probably due to insufficient understanding of the etiopathogenesis of MDD. The aim of this study was to identify the key genes, pathways, and master regulators associated with MDD based on a combination of genomic and transcriptomic data analyses. We performed a transcriptome-wide association study (TWAS) to identify the increase and decrease in transcription of particular genes that can be associated with MDD risk, the results of which were used to perform a pathway enrichment analysis that elucidated the pathways and processes associated with MDD. Besides changes in the metabolism of neurotransmitters, the association of some other processes with MDD was revealed, including changes in phospholipid and glycan metabolism, chromatin remodeling, RNA processing and splicing, and cell-extracellular matrix interaction. The transcriptomic analysis performed for brain regions mostly confirmed genome-level findings. The gene expression changes in the brain related to MDD were mostly sex-specific, and the transcription of many genes was changed in the opposite direction in males and females. Finally, master regulators were found, which are the proteins responsible for the transcriptional regulation of the revealed genes and represent the most important proteins contributing to MDD development.