Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

作者：Signe Penner-Goeke, Melissa Bothe, Nils Kappelmann, Peter Kreitmaier, Ezgi Kaya, Dorothee Pöhlchen, Anne Kühnel, Darina Czamara, BeCOME working group, Laura V. Glaser, Simone Roeh, Maik Ködel, Jose Luis Monteserin Garcia, Christine Rummel, Janine Arloth-Knauer, Laura Diener-Hölzl, B Woelfel, Susann Sauer, Stephan Riesenberg, Michael J. Ziller, Marta Labeur, Sebastiaan H. Meijsing, Elisabeth B. Binder · 发表于：medRxiv · 年份：2022 · DOI：10.1101/2022.05.18.22275090 · 被引用次数：2 · 研究领域：Stress Responses and Cortisol、Receptor Mechanisms and Signaling、Neuroendocrine regulation and behavior

Abstract Exposure to stressful events increases risk for psychiatric disorders. Mechanistic insight into genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3662 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 variants were enriched for those differentially expressed in psychiatric disorders in postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neuro-behavioral traits, including psychiatric disorders. Finally, functional gene scores derived from these variants were significantly associated with differences in physiological stress measures, suggesting that these may alter disease risk by moderating the individual set point of the stress response.