Abstract
Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.
Highlights
Robust sex differences have been reported for stress-related psychiatric disorders, including mood and anxiety disorders, schizophrenia, and post-traumatic stress disorder (PTSD) [1,2,3,4]
Whole blood samples from 289 individuals (93 females [48 patients with depression and 45 healthy controls] and 196 males [81 patients with depression and 115 controls]) recruited at the Max Planck Institute of Psychiatry (MPIP) were analyzed for gene expression levels at baseline and three hours post stimulation by the selective glucocorticoid receptors (GR)-agonist dexamethasone. 11,994 transcripts were entered into the statistical analysis
GR-stimulated gene expression: comparison of males and females First, we assessed the main effects of dexamethasone on gene transcription in a combined differential GR-response gene expression analysis in all participants controlling for sex (Fig. 1)
Summary
Robust sex differences have been reported for stress-related psychiatric disorders, including mood and anxiety disorders, schizophrenia, and post-traumatic stress disorder (PTSD) [1,2,3,4]. MDD-associated transcriptional networks across brain regions are highly disparate between males and females, with sex-stratified results converging with sex differences in a mouse model of chronic social stress [29] Taken together, these findings suggest a role for sex differences in genome function and regulation in sex-specific etiologies of stress-related disorders [30]. Using an animal model of exposure to adversity across development [35], we observed that different combinations of early and adult environments (supportive vs stressful) substantially affect the co-expression structure of these networks in a highly brain region-specific manner [36] This set of eQTLs and regulated transcripts was identified in a male-only cohort. Our results underline the importance of sex-stratified analyses in stress-induced gene-regulation for a better understanding of stress-related psychiatric disorders
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