Análise das alterações transcricionais sexo-específicas do transtorno depressivo maior

Abstract

Major depressive disorder (MDD) is an important neuropsychiatric disorder with high prevalence in Brazil, characterized by persistent depressed mood and/or loss of pleasure for at least two weeks. MDD is a disabling condition that predisposes to other complex pathologies, such as cardiovascular diseases, and may even result in suicide. MDD is more prevalent in women than in men and there are anatomical, immunological, neuronal and hormonal differences, which reflect different prognoses and symptoms between the sexes. However, there is no consensus regarding the MDD transcriptional alterations in men and women, as well as the functional implications of these alterations in the cellular metabolism. Most MDD transcriptional studies explain the disease’s pathophysiology by looking for changes in global gene expression. However, gene expression changes can also occur at the transcript level, as RNA splicing pathways may be altered. The present work seeks to investigate the transcriptional alterations of MDD in women and men through differential gene expression (DGE) analysis, differential transcript expression (DTE) analysis and analysis of differential isoform use (DTU) in post-mortem samples of six brain regions. The set of genes identified in at least one of the three approaches was called transcriptionally altered genes (TAGs), which represent the comprehensive transcriptional alteration profile of MDD. At total, 1075 TAGs were identified mainly in the prefrontal cortex. Approximately half of the transcriptional changes occurred only at the transcript level. We found a near absence of overlap between the altered genes identified in men and the ones identified in women. This indicates that MDD transcriptional alteration profile is sex-specific, considering both the gene- and the transcript-level alterations. We verified alterations in the RNA processing and export pathways in the orbitofrontal cortex of women. Additionally the DDX39B gene, an RNA splicing machinery member, was altered in different brain regions of women and men, respectively. Furthermore, we showed that the ATAT1 gene is altered in multiple brain regions of women and the ABR gene is altered in multiple brain regions of men, constituting potential sex-specific molecular biomarkers for MDD. Therefore, our work shows that the MDD gene expression perturbation occurs through alteration at global gene expression as well as alteration at isoform-level expression.