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Identification of a compound short tandem repeat stretch in the 5′-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia

Molecular Psychiatry volume 6, pages 465–470 (2001)Cite this article

Abstract

The cholecystokinin gene (CCK) is thought to play a role in the pathogenesis of both panic disorder1–4 and schizophrenia.5 In this study, we have extended the 5′-upstream sequence of the CCK gene, and identified a compound short tandem repeat (STR), located approximately −2.2 to −1.8 kb from the cap site. This STR was found to be polymorphic with ten different allele lengths. Case-control studies using 73 panic patients, 305 schizophrenics and 252 controls showed a significant allelic association with panic disorder (P = 0.025), but not with schizophrenia. Dividing the STR alleles into three classes according to length, Long (L), Medium (M) and Short (S), produced strong genotypic (MM) (nominal P = 0.0014) and allelic (M) (nominal P = 0.0079) associations with panic disorder. screening the newly extended promoter region detected not only the previously identified −36c>t and −188a>g single nucleotide polymorphisms (snps) but a new rare snp, −345g>C. Neither of the former two SNPs showed significant association with either panic disorder or schizophrenia. Haplotypic distributions of the STR and SNPs −188 and −36 were significantly different between panic samples and controls (P = 0.0003). These findings suggest that the novel STR or a nearby variant may confer susceptibility to the development of panic disorder.

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References

  1. Bradwejn J, Koszycki D, Meterissian G . Cholecystokinin-tetrapeptide induces panic attacks in patients with panic disorder Can J Psychiatry 1990 35: 83–85

    Article  CAS  Google Scholar 

  2. de Montigny C . Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers: preliminary findings Arch Gen Psychiatry 1989 46: 511–517

    Article  CAS  Google Scholar 

  3. Bradwejn J, Koszycki D, Shriqui C . Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings Arch Gen Psychiatry 1991 48: 603–610

    Article  CAS  Google Scholar 

  4. Bradwejn J, Koszycki D, Couetoux du Tertre A, van Megen H, den Boer J, Westenberg H . The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365, 260, a central cholecystokinin receptor antagonist, in patients with panic disorder Arch Gen Psychiatry 1994 51: 486–493

    Article  CAS  Google Scholar 

  5. Moroji T, Watanabe N, Aoki N, Itoh S . Antipsychotic effects of ceruletide (caerulein) on chronic schizophrenia Arch Gen Psychiatry 1982 39: 485–486

    Article  CAS  Google Scholar 

  6. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG et al. The cross-national epidemiology of panic disorder Arch Gen Psychiatry 1997 54: 305–309

    Article  CAS  Google Scholar 

  7. Skre I, Onstad S, Torgersen S, Lygren S, Kringlen E . A twin study of DSM-III-R anxiety disorders Acta Psychiatr Scand 1993 88: 85–92

    Article  CAS  Google Scholar 

  8. de Weerth A, Pisegna JR, Huppi K, Wank SA . Molecular cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor Biochem Biophys Res Commun 1993 194: 811–818

    Article  CAS  Google Scholar 

  9. Hokfelt T, Rehfeld JF, Skirboll L, Ivemark B, Goldstein M, Markey K . Evidence for coexistence of dopamine and CCK in meso-limbic neurons Nature 1980 285: 476–478

    Article  CAS  Google Scholar 

  10. Wang Z, Valdes J, Noyes R, Zoega T, Crowe RR . Possible association of a cholecystokinin promoter polymorphism (CCK-36CT) with panic disorder Am J Med Genet (Neuropsychiatr Genet) 1998 81: 228–234

    Article  CAS  Google Scholar 

  11. Bowen T, Norton N, Jacobsen NJO, Guy C, Daniels JK, Sanders RD et al. Linked polymorphisms upstream of exons 1 and 2 of the human cholecystokinin gene are not associated with schizophrenia or bipolar disorder Mol Psychiatry 1998 3: 67–71

    Article  CAS  Google Scholar 

  12. Fujii C, Harada S, Ohkoshi N, Hayashi A, Yoshizawa K, Ishizuka C et al. Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease Clin Genet 1999 56: 394–399

    Article  CAS  Google Scholar 

  13. Takahashi Y, Fukushige S, Murotsu T, Matsubara K . Structure of the human cholecystokinin gene and its chromosomal location Gene 1986 50: 353–360

    Article  CAS  Google Scholar 

  14. Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci Ann Hum Genet 1995 59: 97–105

    Article  CAS  Google Scholar 

  15. Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J et al. Investigation of cholecystokinin system genes in panic disorder Mol Psychiatry 1999 4: 284–285

    Article  CAS  Google Scholar 

  16. Hansen TVO, Rehfeld JF, Nielsen FC . Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter Mol Psychiatry 2000 5: 443–447

    Article  CAS  Google Scholar 

  17. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 1996 274: 1527–1531

    Article  CAS  Google Scholar 

  18. Hranilovic D, Schwab SG, Jernej B, Knapp M, Lerer B, Albus M et al. Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings Mol Psychiatry 2000 5: 91–95

    Article  CAS  Google Scholar 

  19. Zhu Q-S, Grimsby J, Chen K, Shih JC . Promoter organization and activity of human monoamine oxidase (MAO) A and B genes J Neurosci 1992 12: 4437–4446

    Article  CAS  Google Scholar 

  20. Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter Hum Genet 1998 103: 273–279

    Article  CAS  Google Scholar 

  21. Deckert J, Catalano M, Syagailo YV, Bosi M, Oklandnova O, Bella DD et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder Hum Mol Genet 1999 8: 621–624

    Article  CAS  Google Scholar 

  22. Pritchard JK, Rosenberg NA . Use of unlinked genetic markers to detect population stratification in association studies Am J Hum Genet 1999 65: 220–228

    Article  CAS  Google Scholar 

  23. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 3rd edn rev American Psychiatric Press: Washington, DC 1987 pp 235–239

  24. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edn American Psychiatric Press: Washington, DC 1994 pp 397–403

  25. Nielsen FC, Pedersen K, Hansen TVO, Rourke IJ, Rehfeld JF . Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors DNA Cell Biol 1996 15: 53–63

    Article  CAS  Google Scholar 

  26. Schneider S, Kueffer J-M, Roessli D, Excoffier L . Arlequin ver.1.1: a Software for Population Genetic Data Analysis Genetics and Biometry Laboratory, University of Geneva, Switzerland

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Acknowledgements

We thank Dr Joanne Meerabux for her critical reading of the manuscript. This study was partly supported by the Grant-in-Aid for Encouragement of Young Scientists, Ministry of Education, Japan (No. 12770554) to Kazuo Yamada.

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Authors and Affiliations

  1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute (BSI), Wako, 351–0198, Saitama, Japan

    E Hattori, M Ebihara, K Yamada, H Ohba & T Yoshikawa

  2. National Sanatorium Minami-Hanamaki Hospital, Hanamaki, 025–0033, Iwate, Japan

    E Hattori & H Shibuya

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  1. E Hattori
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Correspondence to T Yoshikawa.

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Hattori, E., Ebihara, M., Yamada, K. et al. Identification of a compound short tandem repeat stretch in the 5′-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia. Mol Psychiatry 6, 465–470 (2001). https://doi.org/10.1038/sj.mp.4000875

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