Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.
Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Würzburg, Germany.|Department of Psychiatry, Psychosomatics and Psychotherapy, University of Frankfurt, Frankfurt, Germany.
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0000-0002-9421-1292
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Weber
Institute of Psychology, University of Greifswald, Greifswald, Germany.
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J
Richter
Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
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0000-0002-9837-0944
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Straube
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
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Lueken
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
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Domschke
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
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Schartner
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.|Christoph-Dornier-Clinic for Psychotherapy, Münster, Germany.
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B
Klauke
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
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C
Baumann
Institute of Psychology, University of Greifswald, Greifswald, Germany.
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Pané-Farré
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
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CP
Jacob
Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Würzburg, Germany.
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CJ
Scholz
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.|Clinical Research Unit, kbo-Inn-Salzach-Hospital, Wasserburg, Germany.
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Zwanzger
Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany.|Outpatient Treatment Center, University of Bremen, Bremen, Germany.
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T
Lang
Department of Psychology, Humboldt-University of Berlin, Berlin, Germany.
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L
Fehm
Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
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A
Jansen
Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.|Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
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C
Konrad
Department of Psychology, Humboldt-University of Berlin, Berlin, Germany.
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Fydrich
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, Berlin, Germany.
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Wittmann
Department of Clinical Radiology, University of Münster, Münster, Germany.
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B
Pfleiderer
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin, Berlin, Germany.
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Ströhle
Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
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Gerlach
Chair of Clinical and Biological Psychology, School of Social Sciences, University of Mannheim, Mannheim, Germany.
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GW
Alpers
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
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V
Arolt
Department of Psychology, Center of Mental Health, University of Würzburg, Würzburg, Germany.
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P
Pauli
Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.|Centre of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Dresden, Germany.
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Wittchen
School of Medicine, University of St Andrews, St Andrews, Scotland, UK.
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Kent
Institute of Psychology, University of Greifswald, Greifswald, Germany.
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A
Hamm
Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
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T
Kircher
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
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J
Deckert
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Department of Psychiatry, Psychosomatics and Psychotherapy, University of Frankfurt, Frankfurt, Germany.
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0000-0002-0992-634X
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Reif
D000328:Adult; D000483:Alleles; D001007:Anxiety / Q000235:genetics; D001008:Anxiety Disorders / Q000235:genetics; D015982:Bias; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005239:Fear; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics*; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D012307:Risk Factors; D000099052:CRF Receptor, Type 1
D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone