Autosomal sex-biased genetic regulation of the stress response

ABSTRACT Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. How these differences relate to differential risks for stress-related psychiatric disorders is still poorly understood. We have previously identified genomic variants in males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation, and these variants are associated with risk for major depressive disorder (MDD) and other psychiatric disorders. Here, we extend these investigations to a sample of males and females in order to examine sex-biased genetic regulation of the transcriptional response to the stress hormone. 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 (GR-DE) in 93 women and 196 men. We first explored sex differences in the transcriptional GR-response followed by the identification of sex-biased expression quantitative trait loci (eQTLs) by associating gene expression and genotype data stratified by sex. While GR-response transcripts mostly overlapped between males and females, GR-response eQTLs showed strong sex-bias. A total of 804 significant GR-response cis-eQTL bins were found in the joint sample, 648 in females only, and 705 in males only. However, only 46 sex-biased GR-eQTL transcripts (etranscripts) overlapped between the sexes. The sets of associated sex-biased GR eQTL SNPs (eSNPs) were located in different functional genomic elements. Male and female sex-biased etranscripts were enriched within postmortem brain transcriptional profiles associated with MDD specifically in males and females in the cingulate cortex but not other brain regions. Female-biased GR-eSNPs were enriched among SNPs linked to MDD in genome wide association studies (GWAS). Finally, transcriptional sensitive genetic profile scores indexing sex-biased larger transcriptional changes to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). Taken together, while the GR-DE effects were similar between females and males, the genetic moderation of these effects was highly sex-biased and associated with depression-related molecular profiles and symptoms in a similarly sex-biased manner. These results suggest potential of GR-response eQTLs as sex-biased biomarkers of risk for stress-related psychiatric disorders.