Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes

Gottschalk, Michael G.; Richter, Jan; Ziegler, Christiane; Schiele, Miriam A.; Mann, Julia; Geiger, Maximilian J.; Schartner, Christoph; Homola, Gyorgy A.; Alpers, Geoerg W.; Buechel, Christian; Fehm, Lydia; Fydrich, Thomas; Gerlach, Alexander L.; Gloster, Andrew T.; Helbig-Lang, Sylvia; Kalisch, Raffael; Kircher, Tilo; Lang, Thomas; Lonsdorf, Tina B.; Pane-Farre, Christiane A.; Stroehle, Andreas; Weber, Heike; Zwanzger, Peter; Arolt, Volker; Romanos, Marcel; Wittchen, Hans-Ulrich; Hamm, Alfons; Pauli, Paul; Reif, Andreas; Deckert, Jürgen; Neufang, Susanne; Hoefler, Michael und Domschke, Katharina (2019): Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes. In: Translational Psychiatry, Bd. 9, 75

Abstract

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 x 10(-7)), particularly in the female subsample (p = 9.8 x 10(-9)). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 x 10(-4)). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre- CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2158-3188
• Sprache: Englisch