Distinct neurodevelopmental signatures of sex-specific transcriptome-based polygenic risk scores for depression

Major depressive disorder (MDD) impacts females and males differently and post-mortem gene expression profiling reveals distinct transcriptomic signatures of the disorder in each sex. Using genes that are transcriptionally altered in MDD in both sexes, we recently developed a novel transcriptome-based polygenic risk score (tPRS), which had sex-specific associations with brain structure and depressive symptoms in both adolescents and adults. Identifying the neurodevelopmental signatures of genetically-induced shifts toward a depression-like brain transcriptome in each sex during a crucial stage, when sex differences in MDD vulnerability initially manifest, could provide useful information about the developmental pathways of early MDD risk. Leveraging sex-specific MDD gene expression data, we sought to develop female- and male-specific tPRSs (tPRS-F and tPRS-M, respectively) and evaluate their impact on regional cortical thickness, cortical surface area, subcortical volume, and depressive symptoms at baseline and 2-year follow-up in a developmental sample of 5002 adolescents (46.6% female, aged 8.9-11.0). In males, tPRS-M was associated with higher depressive symptoms at both timepoints and thicker left posterior cingulate at follow-up. In females, tPRS-F was associated with lower volumes of the right accumbens area, right caudate, and bilateral hippocampi at follow-up. Subcortical volumes of the right caudate and right hippocampus further mediated an indirect effect of tPRS-F on depressive symptoms. For each sex-specific PRS, no effects emerged in the opposite sex. Our findings suggest that sex-specific depression-like shifts in gene expression may contribute to unique vulnerability phenotypes for future MDD risk via distinct mechanisms in each sex.