232 Brief association letter
Analysis of gastrin-releasing peptide gene and gastrin-releasing peptide receptor gene in patients with agoraphobia Katrin Zimmermanna,*, Heike Görgensb,*, David Bräuerd,f, Franziska Einsled, Barbara Noackc, Stephanie von Kannenb, Maria Grossmannb, Jürgen Hoyerd, Alexander Strobele, Volker Köllnerg, Kerstin Weidnera, Andreas Zieglerh,i, Claudia Hemmelmannh and Hans K. Schackertb A gastrin-releasing peptide receptor (GRPR) knock-out mouse model provided evidence that the gastrin-releasing peptide (GRP) and its neural circuitry operate as a negative feedback-loop regulating fear, suggesting a novel candidate mechanism contributing to individual differences in fear-conditioning and associated psychiatric disorders such as agoraphobia with/without panic disorder. Studies in humans, however, provided inconclusive evidence on the association of GRP and GRPR variations in agoraphobia with/without panic disorder. Based on these findings, we investigated whether GRP and GRPR variants are associated with agoraphobia. Mental disorders were assessed via the Munich-Composite International Diagnostic Interview (M-CIDI) in 95 patients with agoraphobia with/without panic disorder and 119 controls without any mental disorders. A complete sequence analysis of GRP and GRPR was performed in all participants. We found no association of 16 GRP and 7 GRPR variants with agoraphobia with/without panic disorder. Psychiatr Genet 24:232–233 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
A comprehensive understanding of the development and maintenance of fear-related disorders such as agoraphobia should take genetic mechanisms into account that impact on the neural circuitry involved in fear conditioning. In a knockout mouse study by Shumyatsky et al. (2002), gastrin-releasing peptide (GRP) and its receptor (GRPR) were attributed an essential function in the regulation of neural circuitry involved in fear conditioning. Several case–control studies analyzed GRPR in clinical groups with psychiatric disorders (Marui et al., 2004; Seidita et al., 2008); yet, subsequent studies provided inconclusive results (Heidary et al., 1998). Similarly, in a comprehensive association and linkage analysis of 120 panic disorder (73% with agoraphobia) pedigrees, Hodges et al. (2009) reported only a tentative association of two GRP variants with panic disorder. On the basis of these findings, we examined whether variants of GRP and GRPR are associated with agoraphobia in humans. Mental disorders were assessed by the Munich-Composite International Diagnostic Interview (Wittchen and Pfister, 0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Psychiatric Genetics 2014, 24:232–233 Keywords: agoraphobia, gastrin-releasing peptide gene, gastrin-releasing peptide receptor, genetic variants, panic disorder, sequence analysis Departments of aPsychotherapy and Psychosomatic Medicine, bSurgical Research, cConservative Dentistry, University Hospital Carl Gustav Carus, d Institute of Clinical Psychology and Psychotherapy, eInstitute of Psychology II, Technische Universität Dresden, fDepartment of Psychiatry, Städtisches Krankenhaus Dresden-Friedrichstadt, Dresden, gBliestal Clinics, Department of Psychosomatic Medicine and Psychotherapy, Blieskastel, hInstitute for Medical Biometry and Statistics, University Hospital Schleswig-Holstein and iCenter for Clinical Trials, University of Lübeck, Lübeck, Germany Correspondence to David Bräuer, Dipl-Psych, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Hohe Straße 53, 01187 Dresden, Germany Tel: + 49 351 463 36954; fax: + 49 351 463 36955; e-mail: [email protected] *Katrin Zimmermann and Heike Görgens contributed equally to the writing of this article. Received 27 September 2013 Revised 17 December 2013 Accepted 11 April 2014
1996) in 95 patients with agoraphobia (PA) and 119 healthy controls (HC). A complete sequence analysis of coding and adjacent intronic regions of GRP and GRPR was carried out in all participants. There were no significant differences in the genotypic frequencies of 16 GRP polymorphisms between PA and HC. Allele frequencies of − 1082T > C were n = 95/0/0 in the PA group and n = 119/0/0 in the HC group, for − 783G > A frequencies were n = 95/0/0 in the PA group and n = 118/1/0 in the HC group, for − 777G > T frequencies were n = 81/14/0 in the PA group and n = 101/ 18/0 in the HC group, for both − 725G > A and − 724A > G frequencies were n = 58/33/4 in the PA group and n = 71/43/5 in the HC group, and for − 159A > C frequencies were n = 95/0/0 in the PA group and n = 117/0/2 in the HC group. Frequencies for c.10C > A; p.Ser4Arg located in exon 1 were n = 67/23/5 in the PA group and 78/33/8 in the HC group. The frequencies for the variants located in exon 2 were n = 95/0/0 in the PA group and n = 117/2/0 in the HC group for c.330G > T; p. DOI: 10.1097/YPG.0000000000000038
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Analysis of GRP and GRPR gene Zimmermann et al. 233
Ser110Ser, n = 94/1/0 in the PA group and n = 116/3/0 in the HC group for c.363T > C; p.Asp121Asp. Frequencies for c.422_425delGGAA; p.Arg141ThrfsX4 located in exon 3 were n = 87/7/1 in the PA group and n = 110/9/0 in the HC group. The frequencies for the variants located in 3′-UTR were n = 93/2/0 in the PA group and n = 118 /1/0 in the HC group for c.*102_103delTA, n = 95/0/0 in the PA group and n = 118/1/0 in the HC group for c. *195G > A, n = 94/1/0 in the PA group and n = 117/2/0 in the HC group for c.*217C > T, n = 94/1/0 in the PA group and n = 119/0/0 in the HC group, respectively, for c. *243G > T and c.*253A > C, n = 94/1/0 in the PA group and 116/3/0 in the HC group for c.*294A > G. There were no significant differences in the genotypic frequencies of seven GRPR polymorphisms between PA and HC. Allele frequencies of c. − 813A > T were n = 95/0/0 in the PA group and n = 118/0/1 in the HC group and for c. − 673A > G frequencies were n = 95/0/0 in the PA group and n = 118/1/0 in the HC group. Frequencies for c. − 528A > C located in 5′-UTR were n = 95/0/0 in the PA group and 119/0/0 in the HC group. Frequencies for c.396G > A; p.Thr132Thr located in exon 1 were n = 93/2/0 in the PA group and n = 114/5/0 in the HC group. The frequencies for the variants located in exon 2 were n = 43/34/18 in the PA group and n = 60/41/18 in the HC group for both c.453T > C; p. Ser151Ser and c.663T > C; p.Ile221Ile. The frequencies for the variants located in 3′-UTR were n = 95/0/0 in the PA group and n = 119/0/0 in the HC group for c.*148G > C.
For GRP and GRPR, allele frequencies between women and men were not significantly different for all single nucleotide polymorphisms (all P > 0.05). Our results do not argue for a major role of GRP and GRPR variants in agoraphobia. Further research is needed to evaluate the potential impact of deleterious GRP and GRPR mutations on more severe forms of agoraphobia as our cases predominantly had mild forms of the disorder.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References Heidary G, Hampton LL, Schanen NC, Rivkin MJ, Darras BT, Battey J, Francke U (1998). Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome. Am J Med Genet 78:173–175. Hodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O, et al. (2009). Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet 150B:65–73. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi M, Umekage T, et al. (2004). Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism. Brain Dev 26:5–7. Seidita G, Mirisola M, D’Anna RP, Gallo A, Jensen RT, Mantey SA, et al. (2008). Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders. Am J Med Genet 147:807–813. Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, et al. (2002). Identification of a signalling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918. Wittchen H-U, Pfister H (1996). Composite International Diagnostic Interview for ICD-10 and DSM-IV. Frankfurt: Swets and Zeitlinge.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Analysis of gastrin-releasing peptide gene and gastrin-releasing peptide receptor gene in patients with agoraphobia Katrin Zimmermanna,*, Heike Görgensb,*, David Bräuerd,f, Franziska Einsled, Barbara Noackc, Stephanie von Kannenb, Maria Grossmannb, Jürgen Hoyerd, Alexander Strobele, Volker Köllnerg, Kerstin Weidnera, Andreas Zieglerh,i, Claudia Hemmelmannh and Hans K. Schackertb A gastrin-releasing peptide receptor (GRPR) knock-out mouse model provided evidence that the gastrin-releasing peptide (GRP) and its neural circuitry operate as a negative feedback-loop regulating fear, suggesting a novel candidate mechanism contributing to individual differences in fear-conditioning and associated psychiatric disorders such as agoraphobia with/without panic disorder. Studies in humans, however, provided inconclusive evidence on the association of GRP and GRPR variations in agoraphobia with/without panic disorder. Based on these findings, we investigated whether GRP and GRPR variants are associated with agoraphobia. Mental disorders were assessed via the Munich-Composite International Diagnostic Interview (M-CIDI) in 95 patients with agoraphobia with/without panic disorder and 119 controls without any mental disorders. A complete sequence analysis of GRP and GRPR was performed in all participants. We found no association of 16 GRP and 7 GRPR variants with agoraphobia with/without panic disorder. Psychiatr Genet 24:232–233 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
A comprehensive understanding of the development and maintenance of fear-related disorders such as agoraphobia should take genetic mechanisms into account that impact on the neural circuitry involved in fear conditioning. In a knockout mouse study by Shumyatsky et al. (2002), gastrin-releasing peptide (GRP) and its receptor (GRPR) were attributed an essential function in the regulation of neural circuitry involved in fear conditioning. Several case–control studies analyzed GRPR in clinical groups with psychiatric disorders (Marui et al., 2004; Seidita et al., 2008); yet, subsequent studies provided inconclusive results (Heidary et al., 1998). Similarly, in a comprehensive association and linkage analysis of 120 panic disorder (73% with agoraphobia) pedigrees, Hodges et al. (2009) reported only a tentative association of two GRP variants with panic disorder. On the basis of these findings, we examined whether variants of GRP and GRPR are associated with agoraphobia in humans. Mental disorders were assessed by the Munich-Composite International Diagnostic Interview (Wittchen and Pfister, 0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Psychiatric Genetics 2014, 24:232–233 Keywords: agoraphobia, gastrin-releasing peptide gene, gastrin-releasing peptide receptor, genetic variants, panic disorder, sequence analysis Departments of aPsychotherapy and Psychosomatic Medicine, bSurgical Research, cConservative Dentistry, University Hospital Carl Gustav Carus, d Institute of Clinical Psychology and Psychotherapy, eInstitute of Psychology II, Technische Universität Dresden, fDepartment of Psychiatry, Städtisches Krankenhaus Dresden-Friedrichstadt, Dresden, gBliestal Clinics, Department of Psychosomatic Medicine and Psychotherapy, Blieskastel, hInstitute for Medical Biometry and Statistics, University Hospital Schleswig-Holstein and iCenter for Clinical Trials, University of Lübeck, Lübeck, Germany Correspondence to David Bräuer, Dipl-Psych, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Hohe Straße 53, 01187 Dresden, Germany Tel: + 49 351 463 36954; fax: + 49 351 463 36955; e-mail: [email protected] *Katrin Zimmermann and Heike Görgens contributed equally to the writing of this article. Received 27 September 2013 Revised 17 December 2013 Accepted 11 April 2014
1996) in 95 patients with agoraphobia (PA) and 119 healthy controls (HC). A complete sequence analysis of coding and adjacent intronic regions of GRP and GRPR was carried out in all participants. There were no significant differences in the genotypic frequencies of 16 GRP polymorphisms between PA and HC. Allele frequencies of − 1082T > C were n = 95/0/0 in the PA group and n = 119/0/0 in the HC group, for − 783G > A frequencies were n = 95/0/0 in the PA group and n = 118/1/0 in the HC group, for − 777G > T frequencies were n = 81/14/0 in the PA group and n = 101/ 18/0 in the HC group, for both − 725G > A and − 724A > G frequencies were n = 58/33/4 in the PA group and n = 71/43/5 in the HC group, and for − 159A > C frequencies were n = 95/0/0 in the PA group and n = 117/0/2 in the HC group. Frequencies for c.10C > A; p.Ser4Arg located in exon 1 were n = 67/23/5 in the PA group and 78/33/8 in the HC group. The frequencies for the variants located in exon 2 were n = 95/0/0 in the PA group and n = 117/2/0 in the HC group for c.330G > T; p. DOI: 10.1097/YPG.0000000000000038
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Analysis of GRP and GRPR gene Zimmermann et al. 233
Ser110Ser, n = 94/1/0 in the PA group and n = 116/3/0 in the HC group for c.363T > C; p.Asp121Asp. Frequencies for c.422_425delGGAA; p.Arg141ThrfsX4 located in exon 3 were n = 87/7/1 in the PA group and n = 110/9/0 in the HC group. The frequencies for the variants located in 3′-UTR were n = 93/2/0 in the PA group and n = 118 /1/0 in the HC group for c.*102_103delTA, n = 95/0/0 in the PA group and n = 118/1/0 in the HC group for c. *195G > A, n = 94/1/0 in the PA group and n = 117/2/0 in the HC group for c.*217C > T, n = 94/1/0 in the PA group and n = 119/0/0 in the HC group, respectively, for c. *243G > T and c.*253A > C, n = 94/1/0 in the PA group and 116/3/0 in the HC group for c.*294A > G. There were no significant differences in the genotypic frequencies of seven GRPR polymorphisms between PA and HC. Allele frequencies of c. − 813A > T were n = 95/0/0 in the PA group and n = 118/0/1 in the HC group and for c. − 673A > G frequencies were n = 95/0/0 in the PA group and n = 118/1/0 in the HC group. Frequencies for c. − 528A > C located in 5′-UTR were n = 95/0/0 in the PA group and 119/0/0 in the HC group. Frequencies for c.396G > A; p.Thr132Thr located in exon 1 were n = 93/2/0 in the PA group and n = 114/5/0 in the HC group. The frequencies for the variants located in exon 2 were n = 43/34/18 in the PA group and n = 60/41/18 in the HC group for both c.453T > C; p. Ser151Ser and c.663T > C; p.Ile221Ile. The frequencies for the variants located in 3′-UTR were n = 95/0/0 in the PA group and n = 119/0/0 in the HC group for c.*148G > C.
For GRP and GRPR, allele frequencies between women and men were not significantly different for all single nucleotide polymorphisms (all P > 0.05). Our results do not argue for a major role of GRP and GRPR variants in agoraphobia. Further research is needed to evaluate the potential impact of deleterious GRP and GRPR mutations on more severe forms of agoraphobia as our cases predominantly had mild forms of the disorder.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References Heidary G, Hampton LL, Schanen NC, Rivkin MJ, Darras BT, Battey J, Francke U (1998). Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome. Am J Med Genet 78:173–175. Hodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O, et al. (2009). Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet 150B:65–73. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi M, Umekage T, et al. (2004). Gastrin-releasing peptide receptor (GRPR) locus in Japanese subjects with autism. Brain Dev 26:5–7. Seidita G, Mirisola M, D’Anna RP, Gallo A, Jensen RT, Mantey SA, et al. (2008). Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders. Am J Med Genet 147:807–813. Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, et al. (2002). Identification of a signalling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918. Wittchen H-U, Pfister H (1996). Composite International Diagnostic Interview for ICD-10 and DSM-IV. Frankfurt: Swets and Zeitlinge.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
