Sex-specific gene expression differences in the prefrontal cortex of major depressive disorder individuals.

• Identified 1169 transcriptionally altered genes (TAGs) linked to major depressive disorder. • Nearly 50% of TAGs exhibited transcript-level alterations, primarily in prefrontal areas. • We identified evidence for a systematic transcript-level alteration in MDD, which follows a sex-specific pattern. Major depressive disorder (MDD) is a leading global cause of disability, being more prevalent in females, possibly due to molecular and neuronal pathway differences between females and males. However, the connection between transcriptional changes and MDD remains unclear. We identified transcriptionally altered genes (TAGs) in MDD through gene and transcript expression analyses, focusing on sex-specific differences. Analyzing 263 brain samples from both sexes, we conducted differential gene expression, differential transcript expression, and differential transcript usage analyses, revealing 1169 unique TAGs, primarily in the prefrontal areas, with nearly half exhibiting transcript-level alterations. Females showed notable RNA splicing and export process disruptions in the orbitofrontal cortex, alongside altered DDX39B gene expression in five of the six brain regions in both sexes. Our findings suggest that disruptions in RNA processing pathways may play a vital role in MDD. [ABSTRACT FROM AUTHOR]