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Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Preclinical studies point to a pivotal role of the orexin 1 (OX<jats:sub>1<\/jats:sub>) receptor in arousal and fear learning and therefore suggest the <jats:italic>HCRTR1<\/jats:italic> 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 <jats:italic>HCRTR1<\/jats:italic> C\/T Ile408Val gene variant (rs2271933) for association with PD\/AG in two independent case-control samples (total <jats:italic>n<\/jats:italic>\u2009=\u2009613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD\/AG patients (<jats:italic>n<\/jats:italic>\u2009=\u2009189), as well as with respect to agoraphobic cognitions (ACQ) (<jats:italic>n<\/jats:italic>\u2009=\u2009483 patients, <jats:italic>n<\/jats:italic>\u2009=\u20092382 healthy subjects), fMRI alerting network activation in healthy subjects (<jats:italic>n<\/jats:italic>\u2009=\u200994), and a behavioral avoidance task in PD\/AG pre- and post-CBT (<jats:italic>n<\/jats:italic>\u2009=\u2009271). The <jats:italic>HCRTR1<\/jats:italic> rs2271933 T allele was associated with PD\/AG in both samples independently, and in their meta-analysis (<jats:italic>p<\/jats:italic>\u2009=\u20094.2\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>), particularly in the female subsample (<jats:italic>p<\/jats:italic>\u2009=\u20099.8\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup>). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: <jats:italic>p<\/jats:italic>\u2009=\u20097.5\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>). 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 <jats:italic>HCRTR1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41398-019-0415-8","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T17:03:59Z","timestamp":1549299839000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder\/agoraphobia, CBT treatment response and fear-related intermediate phenotypes"],"prefix":"10.1038","volume":"9","author":[{"given":"Michael 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