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Abstract

Stress and exposure to stressful life events are some of the strongest risk factors for the development of psychiatric disorders. While it is known that genetic factors play an important role in one?s response to stress, the genetic variants driving differences in the stress response have yet to be determined. Using an expression trait quantitative loci (eQTL) approach, previous research from our group identified over 3600 genetic variants associated with altered transcriptional activity upon activation of the glucocorticoid receptor (GR), a key transcription factor in the stress response system. These variants (GR-eQTLs) were enriched in GR binding sites and putative regulatory elements, and predicted case-control status for major depressive disorder, as well as amygdala activity in an emotional reactivity task. However, due to linkage disequilibrium, the functional variants driving these transcriptional changes remain unidentified.

In order to identify which of the GR-eQTLs had a functional effect on GR mediated transcription, we performed STARR-sequencing, an approach allowing thousands of DNA sequences to be assessed for regulatory element activity in parallel. This allowed us to determine the effect of each GR-eQTL on transcriptional activity at baseline and after GR activation with dexamethasone (dex) in GR18 and U138MG cells. STARR-seq revealed that 1220 variants were located in active regulatory elements, either at baseline or after dex. Of these, 547 variants show differential transcriptional activity after dex treatment (DREs). These were enriched in GR-binding sites determined by ChIP-seq, as well as chromatin loop anchor points. Next, DREs with allele dependent activity at baseline and after dex were identified. We found 165 DREs to show allele dependent activity at baseline, and 172 DREs after dex. Both the baseline and dex functional variants showed a significant overlap with variants nominally associated with psychiatric disorders from the latest psychiatric cross disorder meta-analysis GWAS. Furthermore, using Mendelian Randomization, nineteen and eleven DREs with allele-dependent activity in the dex and veh condition, respectively, were identified to have a putative causal effect on psychiatric disorders. These results suggest that the loci modulating the transcriptomic response to stress are putatively causally associated with psychopathology.