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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
Keywords Snps ; Starr-seq ; Glucocorticoids ; Psychiatric Disorders; Cortisol Response; Genetic Risk; Receptor; Binding; Depression; Variants; Brain; Loci; Association; Motifs
Language english
Publication Year 2023
HGF-reported in Year 2023
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, Pages: , Article Number: e2305773120 Supplement: ,
Publisher National Academy of Sciences
Publishing Place 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506700-001
Grants Deutsche Forschungsgemeinschaft
Joachim Herz Stiftung Add-on Fellowship for Interdisciplinary Life Science
Hopefor Depression Research Foundation
DOI 10.1073/pnas.2305773120
WOS ID 001158695900020
WOS ID 001166517700014
PubMed ID 38011552
Erfassungsdatum 2023-12-19
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