Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

• Published in: Neuron (Cambridge, Mass.) Vol. 86; no. 5; pp. 1189 - 1202
• Main Authors: Arloth, Janine, Bogdan, Ryan, Weber, Peter, Frishman, Goar, Menke, Andreas, Wagner, Klaus V., Schmidt, Mathias V., Karbalai, Nazanin, Czamara, Darina, Altmann, Andre, Trümbach, Dietrich, Wurst, Wolfgang, Mehta, Divya, Carey, Caitlin E., Conley, Emily Drabant, Ripke, Stephan, Wray, Naomi R., Lewis, Cathryn M., Hamilton, Steven P., Blackwood, Douglas H.R., Boomsma, Dorret I., Cichon, Sven, Heath, Andrew C., Holsboer, Florian, Muglia, Pierandrea, Noethen, Markus M., Penninx, Brenda P., Pergadia, Michele L., Potash, James B., Lin, Danyu, Müller-Myhsok, Bertram, Shi, Jianxin, Steinberg, Stacy, Grabe, Hans J., Lichtenstein, Paul, Perlis, Roy H., Preisig, Martin, Smoller, Jordan W., Kutalik, Zoltan, Tansey, Katherine E., Teumer, Alexander, Bettecken, Thomas, Binder, Elisabeth B., Breuer, René, Castro, Victor M., Coryell, William H., Craddock, Nick, Degenhardt, Franziska, Fava, Maurizio, Frank, Josef, Gainer, Vivian S., Gallagher, Patience J., Gordon, Scott D., Goryachev, Sergey, Guipponi, Michel, Henders, Anjali K., Hickie, Ian B., Hottenga, Jouke Jan, Jones, Ian, Jones, Lisa, Jung-Ying, Tzeng, Knowles, James A., Kohane, Isaac S., Kohli, Martin A., Korszun, Ania, Landen, Mikael, Lawson, William B., Lewis, Glyn, MacIntyre, Donald, Maier, Wolfgang, Mattheisen, Manuel, McGrath, Patrick J., McIntosh, Andrew, McLean, Alan, Montgomery, Grant M., Murphy, Shawn N., Nauck, Matthias, O’Donovan, Michael, Oskarsson, Högni, Pedersen, Nancy, Schulz, Andrea, Schulze, Thomas G., Shyn, Stanley I., Sigurdsson, Engilbert, Slager, Susan L., Smit, Johannes H., Stefansson, Hreinn, Steffens, Michael, Tozzi, Federica, Treutlein, Jens, Völzke, Henry, Weilburg, Jeffrey B., Willemsen, Gonneke, Neale, Benjamin, Daly, Mark, Levinson, Douglas F., Hariri, Ahmad R., Binder, Elisabeth B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.06.2015; Elsevier Limited; Cell Press
• Subjects: Animals; Attention deficit hyperactivity disorder; Binding sites; Brain - physiology; Cohort Studies; Forecasting; Gene expression; Gene Regulatory Networks - genetics; Genetic Variation - genetics; Humans; Male; Medicin och hälsovetenskap; Mental Disorders - diagnosis; Mental Disorders - genetics; Mice; Mice, Inbred C57BL; Polymorphism, Single Nucleotide - genetics; Risk Factors; Stress, Psychological - diagnosis; Stress, Psychological - genetics; Transcriptome - genetics; Working groups
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2015.05.034

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. [Display omitted] •SNPs in long-range enhancers alter the transcriptional response of GR target genes•These functional SNPs predict risk for psychiatric but not other medical disorders•These variants are associated with differential neural circuit responses to threat•GR transcripts are strongly co-expressed and regulated in the brain of animal models Using a stimulated eQTL approach, Arloth et al. show that common genetic variants that alter the initial transcriptome response to stress hormone receptor activation also cumulatively increase the risk for stress-related psychiatric disorders and predict a threat response from the amygdala.