Signe Penner-Goeke, Melissa Bothe, Nils Rek, Peter Kreitmaier, Dorothee Pöhlchen et al.
Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into the genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these functional variants were enriched for those differentially expressed in psychiatric disorders in the postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neurobehavioral traits, including major depression and other psychiatric disorders. Finally, a functional gene score derived from these variants was significantly associated with differences in the physiological stress response, suggesting that these variants may alter disease risk by moderating the individual set point of the stress response.
Signe Penner-Goeke, Melissa Bothe, Nils Rek, Peter Kreitmaier, Dorothee Pöhlchen, Anne Kühnel, Laura V. Glaser, Ezgi Kaya, Anthi C. Krontira, Simone Röh, Darina Czamara, Maik Ködel, Jose Monteserin-Garcia, Laura Diener, Barbara Wölfel, Susann Sauer, Christine Rummel, Stephan Riesenberg, Janine Arloth-Knauer, Michael Ziller, Marta Labeur, Sebastiaan Meijsing, Elisabeth B. Binder. High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders. 2023-11-27. https://doi.org/10.1073/pnas.2305773120
An episomal synthetic STARR-seq library tested 201-bp reference and alternative alleles centered on 3,662 dexamethasone-responsive eSNP candidates, together with positive and negative control inserts, in U2OS-GR cells. This experiment compares 100 nM dexamethasone for 4 h with a 0.001% ethanol vehicle control; the packaged table contains published DRE and SNP-DRE results passing the reported statistical filters.
An episomal synthetic STARR-seq library tested 201-bp reference and alternative alleles centered on 3,662 dexamethasone-responsive eSNP candidates, together with positive and negative control inserts, in U138MG cells. This experiment compares 100 nM dexamethasone for 4 h with a 0.001% ethanol vehicle control; the packaged table contains published DRE and SNP-DRE results passing the reported statistical filters.
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