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

Penner-Goeke, Signe; Bothe, Melissa; Rek, Nils; Kreitmaier, Peter; Poehlchen, Dorothee; Kühnel, Anne; Glaser, Laura V.; Kaya, Ezgi; Krontira, Anthodesmi; Roeh, Simone; Czamara, Darina; Ködel, Maik; Monteserin-Garcia, Jose; Diener, Laura; Woelfel, Barbara; Sauer, Susann; Rummel, Christine; Riesenberg, Stephan; Arloth-Knauer, Janine; Ziller, Michael; Labeur, Marta; Meijsing, Sebastiaan; Binder, Elisabeth B.

doi:10.1073/pnas.2305773120

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

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Penner-Goeke, Signe
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons227413

Rek, Nils
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262423

Poehlchen, Dorothee
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262197

Kühnel, Anne
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263198

Kaya, Ezgi
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262245

Krontira, Anthodesmi
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons128467

Roeh, Simone
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80291

Czamara, Darina
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222056

Ködel, Maik
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80447

Monteserin-Garcia, Jose
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222280

Diener, Laura
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80595

Woelfel, Barbara
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons226837

Sauer, Susann
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons262462

Rummel, Christine
IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons98244

Arloth-Knauer, Janine
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons203557

Ziller, Michael
RG Genomics of Complex Diseases, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80417

Labeur, Marta
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80272

Binder, Elisabeth B.
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Penner-Goeke, S., Bothe, M., Rek, N., Kreitmaier, P., Poehlchen, D., Kühnel, A., et al. (2023). High- throughput screening of glucocorticoid- induced enhancer activity reveals mechanisms of stress- related psychiatric disorders. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(49): e2305773120. doi:10.1073/pnas.2305773120.

Cite as: https://hdl.handle.net/21.11116/0000-000E-A630-0

Abstract

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.