High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders

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 qua...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (49), p.e2305773120-e2305773120
Main Authors: Penner-Goeke, Signe, Bothe, Melissa, Rek, Nils, Kreitmaier, Peter, Pöhlchen, Dorothee, Kühnel, Anne, Glaser, Laura V, Kaya, Ezgi, Krontira, Anthi C, Röh, Simone, Czamara, Darina, Ködel, Maik, Monteserin-Garcia, Jose, Diener, Laura, Wölfel, Barbara, Sauer, Susann, Rummel, Christine, Riesenberg, Stephan, Arloth-Knauer, Janine, Ziller, Michael, Labeur, Marta, Meijsing, Sebastiaan, Binder, Elisabeth B
Format: Article
Language:English
Subjects:
Biological Sciences
Disorders
Gene mapping
Genetic diversity
Genetic factors
Genetic Predisposition to Disease
Genetic variance
Genome-Wide Association Study
Glucocorticoids
Health risks
High-throughput screening
High-Throughput Screening Assays
Humans
Mental disorders
Mental Disorders - genetics
Nucleotides
Phenotypes
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Regulatory sequences
Regulatory Sequences, Nucleic Acid
Single-nucleotide polymorphism
Stress (physiology)
Stress response
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2305773120