Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.
Bottom Line: One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation.Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells.Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger.
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.Show MeSH
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Mentions: Besides their functional characterization, an important question was to assess whether the genetic variants that alter the immediate transcriptional response to GR activation (GR-response eSNPs) would also be associated with risk for stress-related psychiatric disorder. To assess this, we first tested whether our GR-response eSNPs were overrepresented among SNPs associated with MDD in the genome-wide association study (GWAS) results of the Psychiatric Genomics Consortium (PGC), which includes approximately 9,000 cases and the same number of controls (Ripke et al., 2013). Among nominally associated loci with MDD (at meta-analysis p value ≤ 0.05), 282 SNPs also represent a GR-response eSNP. Permutation analysis (see Experimental Procedures) predicted an expected mean overlap of 210 SNPs from 1,000 randomly selected SNP sets (fold enrichment = 1.34, permutation-based FDR < 0.001; Figure 5A). We next investigated whether GR-response eSNPs were also enriched over baseline eSNPs, as SNPs associated with transcriptional changes have been shown to be more enriched in GWASs in general (Roussos et al., 2014). Again the mean overlap for 1,000 permuted baseline cis-eSNP sets (218 SNPs) was significantly lower than the actual overlap of GR-response eSNPs (fold enrichment = 1.29, permutation-based FDR < 0.001; Figure 5A). These enrichments remain significant when using only the tag eSNPs (n = 285) to control for possible confounding due to linkage disequilibrium (LD) structure (fold enrichment = 1.31, permutation-based FDR = 0.082).
Affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.