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A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder

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Abstract

Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton’s rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using χ 2 statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed.

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References

  • Brown SM, Peet E, Manuck SB, Williamson DE, Dahl RE, Ferrell RE, Hariri AR (2005) A regulatory variant of the human tryptophan hydroxylase 2 gene biases amygdala reactivity. Mol Psychiatry 10:884–888 805

    Article  PubMed  CAS  Google Scholar 

  • Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP (2005) Amygdala responsiveness is modulated by tryptophan hydroxylase 2 gene variation. J Neural Trans 112:1479–1485. doi:10.1007/s00702-005-0391-4

    Article  CAS  Google Scholar 

  • Chaouloff F (1993) Physiopharmacological interactions between stress hormones and central serotonergic systems. Brain Res Rev 18:1–32. doi:10.1016/0165-0173(93)90005-K

    Article  PubMed  CAS  Google Scholar 

  • De Angelis L (2002) 5-HT2A antagonists in psychiatric disorders. Curr Opin Invest Drugs 3:106–112

    Google Scholar 

  • De Luca V, Likhodi O, Van Tol HH, Kennedy JL, Wong AH (2005) Tryptophan hydroxylase 2 gene expression and romoter polymorphisms in bipolar disorder and schizophrenia. Psychopharmacol 183:378–382. doi:10.1007/s00213-005-0191-4

    Article  CAS  Google Scholar 

  • Dillon DJ, Gorman JM, Liebowitz MR, Fyer AJ, Klein DF (1987) Measurement of lactate-induced panic and anxiety. Psychiatry Res 20:97–105. doi:10.1016/0165-1781(87)90002-3

    Article  PubMed  CAS  Google Scholar 

  • Eaton WW, Kessler RC, Wittchen HU, Magee WJ (1994) Panic and panic disorder in the United States. Am J Psychiatry 151:413–420

    PubMed  CAS  Google Scholar 

  • Fehr C, Schleicher A, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N (2001) Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy. Prog Neuropsychopharmacol Biol Psychiatry 25:965–982. doi:10.1016/S0278-5846(01)00171-3

    Article  PubMed  CAS  Google Scholar 

  • First M, Spitzer RL, Gibbon M, William JB (1998) Structured clinical interview for DSM-IV axis I disorder-patient edition (SCID-I/P, version 2.0). Biometrics Research Department, New York State Psychiatric Institute, New York

    Google Scholar 

  • Grant BF, Hasin DS, Stinson FS, Dawson DA, Goldstein RB, Smith S, Huang B, Saha TD (2006) The epidemiology of DSM-IV panic disorder and agoraphobia in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 67:363–374

    Article  PubMed  Google Scholar 

  • Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Müller J, Zeng Y, Markert C, Escher A, Wendland J, Reif A et al (2007) Tryptophan hydroxylase 2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol 10:309–320. doi:10.1017/S1461145706007437

    Article  PubMed  CAS  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    Article  PubMed  CAS  Google Scholar 

  • Han L, Nielsen DA, Rosenthal NE, Jefferson K, Kaye W, Murphy D, Altemus M, Humphries J, Cassano G, Rotondo A et al (1999) No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder, obsessive-compulsive disorder, anorexia nervosa, and alcoholism. Biol Psychiatry 45:615–619. doi:10.1016/S0006-3223(98)00122-X

    Article  PubMed  CAS  Google Scholar 

  • Hettema JM, Neale MC, Kendler KS (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578. doi:10.1176/appi.ajp.158.10.1568

    Article  PubMed  CAS  Google Scholar 

  • Higashi S, Ohnuma T, Shibata N, Higashi M, Matsubara Y, Arai H (2007) No genetic association between tryptophan hydroxylase 2 gene polymorphisms and Japanese schizophrenia. Psychiatr Genet 17:123. doi:10.1097/YPG.0b013e328011c01a

    Article  PubMed  Google Scholar 

  • Kawahara H, Yoshida M, Yokoo H, Nishi M, Tanaka M (1993) Psychological stress increases serotonin release in the rat amygdala and prefrontal cortex assessed by in vivo microdialysis. Neurosci Lett 162:81–84. doi:10.1016/0304-3940(93)90565-3

    Article  PubMed  CAS  Google Scholar 

  • Kim W, Choi YH, Yoon KS, Cho DY, Pae CU, Woo JM (2006) Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis, clinical features and treatment outcome of panic disorder in the Korean population. Prog Neuropsychopharmacol Biol Psychiatry 30:1413–1418. doi:10.1016/j.pnpbp.2006.05.017

    Article  PubMed  CAS  Google Scholar 

  • LeDoux JE, Cicchetti P, Xagoraris A, Romanski LM (1990) The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci 10:1062–1069

    PubMed  CAS  Google Scholar 

  • Lim YJ, Yu BH, Kim JH (2007) Korean panic disorder severity scale: construct validity by confirmatory factor analysis. Depress Anxiety 24:95–102. doi:10.1002/da.20206

    Article  PubMed  CAS  Google Scholar 

  • Lin YM, Chao SC, Chen TM, Lai TJ, Chen JS, Sun HS (2007) Association of functional polymorphisms of the human tryptophan hydroxylase 2 gene with risk for bipolar disorder in Han Chinese. Arch Gen Psychiatry 64:1015–1024. doi:10.1001/archpsyc.64.9.1015

    Article  PubMed  CAS  Google Scholar 

  • Lopez de Lara C, Brezo J, Rouleau G, Lesage A, Dumont M, Alda M, Benkelfat C, Turecki G (2007) Effect of tryptophan hydroxylase 2 gene variants on suicide risk in major depression. Biol Psychiatry 62:72–80. doi:10.1016/j.biopsych.2006.09.008

    Article  PubMed  CAS  Google Scholar 

  • Maron E, Lang A, Tasa G, Liivlaid L, Töru I, Must A, Vasar V, Shlik J (2005) Associations between serotonin-related gene polymorphisms and panic disorder. The international journal of neuropsychopharmacology/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 8:261–266

    CAS  Google Scholar 

  • Maron E, Tõru I, Must A, Tasa G, Toover E, Vasar V, Lang A, Shlik J (2007) Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder. Neurosci Lett 411:180–184. doi:10.1016/j.neulet.2006.09.060

    Article  PubMed  CAS  Google Scholar 

  • Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P, Fritze J, Wagner G, Peikert G, Wenda B et al (2006a) The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder. J Psychopharmacol 20:547–552. doi:10.1177/0269881106059704

    Article  PubMed  Google Scholar 

  • Mössner R, Walitza S, Geller F, Scherag A, Gutknecht L, Jacob C, Bogusch L, Remschmidt H, Simons M, Herpertz-Dahlmann B et al (2006b) Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase 2 gene in children and adolescents with obsessive-compulsive disorder. Int J Neuropsychopharmacol 9:437–442. doi:10.1017/S1461145705005997

    Article  PubMed  CAS  Google Scholar 

  • Mössner R, Müller-Vahl KR, Döring N, Stuhrmann M (2007) Role of the novel tryptophan hydroxylase 2 gene in Tourette syndrome. Mol Psychiatry 12:617–619. doi:10.1038/sj.mp.4002004

    Article  PubMed  CAS  Google Scholar 

  • Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic M (1997) Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA 94:5308–5313. doi:10.1073/pnas.94.10.5308

    Article  PubMed  CAS  Google Scholar 

  • Nutt DJ (1998) Antidepressants in panic disorder: clinical and preclinical mechanisms. J Clin Psychiatry 59(8):24–28 discussion 29

    PubMed  CAS  Google Scholar 

  • Papp LA, Martinez JM, Klein DF, Coplan JD, Norman RG, Cole R, de Jesus MJ, Ross D, Goetz R, Gorman JM (1997) Respiratory psychophysiology of panic disorder: three respiratory challenges in 98 subjects. Am J Psychiatry 154:1557–1565

    PubMed  CAS  Google Scholar 

  • Reiss S, Peterson RA, Gursky DM, McNally R (1986) Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther 24:1–8. doi:10.1016/0005-7967(86)90143-9

    Article  PubMed  CAS  Google Scholar 

  • Reuter M, Kuepper Y, Hennig J (2007) Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. Int J Neuropsychopharmacol 10:401–404. doi:10.1017/S1461145706007073

    Article  PubMed  CAS  Google Scholar 

  • Savander V, Miettinen R, Ledoux JE, Pitkänen A (1997) Lateral nucleus of the rat amygdala is reciprocally connected with basal and accessory basal nuclei: a light and electron microscopic study. J Neurosci 77:767–781. doi:10.1016/S0306-4522(96)00513-1

    Article  CAS  Google Scholar 

  • Schruers K, Klaassen T, Pols H, Overbeek T, Deutz NE, Griez E (2000) Effects of tryptophan depletion on carbon dioxide provoked panic in panic disorder patients. Psychiatry Res 93:179–187. doi:10.1016/S0165-1781(00)00117-7

    Article  PubMed  CAS  Google Scholar 

  • Schruers K, van Diest R, Overbeek T, Griez E (2002) Acute L-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry Res 113:237–243. doi:10.1016/S0165-1781(02)00262-7

    Article  PubMed  CAS  Google Scholar 

  • Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, Gorman JM, Papp LA (1997) Multicenter collaborative panic disorder severity scale. Am J Psychiatry 154:1571–1575

    PubMed  CAS  Google Scholar 

  • Shear MK, Rucci P, Williams J, Frank E, Grochocinski V, Vander Bilt J, Houck P, Wang T (2001) Reliability and validity of the panic disorder severity scale: replication and extension. J Psychiatr Res 35:293–296. doi:10.1016/S0022-3956(01)00028-0

    Article  PubMed  CAS  Google Scholar 

  • Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z (2005) Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol Psychiatry 10:944–949. doi:10.1038/sj.mp.4001698

    Article  PubMed  CAS  Google Scholar 

  • Spielberger CD (1983) STAI: manual for the stait-trait anxiety inventory. Consulting Psychologists Press, Palo Alto

    Google Scholar 

  • Stutzmann GE, McEwen BS, LeDoux JE (1998) Serotonin modulation of sensory inputs to the lateral amygdala: dependency on corticosterone. J Neurosci 18:9529–9538

    PubMed  CAS  Google Scholar 

  • Taylor S, Koch WJ, Crockett DJ (1991) Anxiety sensitivity, trait anxiety, and the anxiety disorders. J Anxiety Disorders 5:293–311. doi:10.1016/0887-6185(91)90030-W

    Article  Google Scholar 

  • Telch MJ, Shermis MD, Lucas JA (1989) Anxiety sensitivity: unitary personality trait or domain-specific appraisals? J Anxiety Disorders 3:25–32. doi:10.1016/0887-6185(89)90026-1

    Article  Google Scholar 

  • Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673–1680. doi:10.1016/S0006-2952(03)00556-2

    Article  PubMed  CAS  Google Scholar 

  • Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76. doi:10.1126/science.1078197

    Article  PubMed  CAS  Google Scholar 

  • Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J et al (1997) The cross-national epidemiology of panic disorder. Arch Gen Psychiatry 54:305–309

    PubMed  CAS  Google Scholar 

  • Yoon HK, Yang JC, Lee HJ, Kim YK (2008) The association between serotonin-related gene polymorphisms and panic disorder. J Anxiety Disord 22:1529–1534

    Article  PubMed  Google Scholar 

  • Zill P, Büttner A, Eisenmenger W, Bondy B, Ackenheil M (2004a) Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur Neuropsychopharmacol 14:282–284. doi:10.1016/j.euroneuro.2003.10.002

    Article  PubMed  CAS  Google Scholar 

  • Zill P, Büttner A, Eisenmenger W, Möller HJ, Bondy B, Ackenheil M (2004b) Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 56:581–586

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A040042).

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Authors and Affiliations

  1. Department of Psychiatry, College of Medicine, Ansan Hospital, Korea University, Gojan Dong, 516, Ansan City, Kyunggi Province, 425020, South Korea

    Yong-Ku Kim, Jung-A Hwang & Ho-Kyoung Yoon

  2. Department of Psychiatry, College of Medicine, Anam Hospital, Korea University, 126-1, 5-Ka, Anam-Dong, Sungbuk-Ku, Seoul, 136-705, South Korea

    Heon-Jeong Lee

  3. Department of Psychiatry, College of Medicine, Chonbuk University, Jeonju, South Korea

    Jong-Chul Yang

  4. Division of Brain Korea 21 Biomedical Science, Korea University, Seoul, South Korea

    Yong-Ku Kim

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  1. Yong-Ku Kim
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Correspondence to Ho-Kyoung Yoon.

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Kim, YK., Lee, HJ., Yang, JC. et al. A Tryptophan Hydroxylase 2 Gene Polymorphism is Associated with Panic Disorder. Behav Genet 39, 170–175 (2009). https://doi.org/10.1007/s10519-008-9254-8

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