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Penner-Goeke, S.* ; Bothe, M.* ; Rek, N.* ; Kreitmaier, P. ; Pöhlchen, D.* ; Kühnel, A.* ; Glaser, L.* ; Kaya, E.* ; Krontira, A.C.* ; Röh, S.* ; Czamara, D.* ; Ködel, M.* ; Monteserin-Garcia, J.L.* ; Diener, L.* ; Wölfel, B.* ; Sauer, S.* ; Rummel, C.* ; Riesenberg, S.* ; Arloth-Knauer, J.* ; Ziller, M.J.* ; Labeur, M.* ; Meijsing, S.* ; Binder, E.B.*

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

Proc. Natl. Acad. Sci. U.S.A. 120:e2305773120 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Snps ; Starr-seq ; Glucocorticoids ; Psychiatric Disorders; Cortisol Response; Genetic Risk; Receptor; Binding; Depression; Variants; Brain; Loci; Association; Motifs

ISSN (print) / ISBN 0027-8424

e-ISSN 1091-6490

Journal Proceedings of the National Academy of Sciences of the United States of America

Quellenangaben Volume: 120, Issue: 49, Article Number: e2305773120

Publisher National Academy of Sciences

Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)

Grants Deutsche Forschungsgemeinschaft
Joachim Herz Stiftung Add-on Fellowship for Interdisciplinary Life Science
Hopefor Depression Research Foundation