Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Feature Review
  • Published:

Advances in molecular genetics of panic disorder

Molecular Psychiatry volume 15, pages 681–701 (2010)Cite this article

Subjects

Abstract

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. Although the data from twin and family studies suggest an involvement of genetic factors in the familial transmission of PD with the heritability estimate near 40%, the genetic substrate underlying panicogenesis is not yet understood. The linkage studies so far have suggested that chromosomal regions 13q, 14q, 22q, 4q31–q34, and probably 9q31 are associated with the transmission of PD phenotypes. To date, more than 350 candidate genes have been examined in association studies of PD, but most of these results remain inconsistent, negative, or not clearly replicated. Only Val158Met polymorphism of the catechol-O-methyltransferase gene has been implicated in susceptibility to PD by several studies in independent samples and confirmed in a recent meta-analysis. However, the specific role of this genetic variation in PD requires additional analysis considering its gender- and ethnicity-dependent effect and putative impact on cognitive functions. The recent advantages in bioinformatics and genotyping technologies, including genome-wide association and gene expression methods, provide the means for far more comprehensive discovery in PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current controversies to more definitive findings.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR (Text Revision). American Psychiatric Association: Washington, DC, 2000.

  2. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE . The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2006; 63: 415–424.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Roy-Byrne PP, Craske MG, Stein MB . Panic disorder. Lancet 2006; 368: 1023–1032.

    Article  PubMed  Google Scholar 

  4. Hettema JM, Neale MC, Myers JM, Prescott CA, Kendler KS . A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry 2006; 163: 857–864.

    Article  PubMed  Google Scholar 

  5. Clark DM . A cognitive approach to panic. Behav Res Ther 1986; 24: 461–470.

    Article  CAS  PubMed  Google Scholar 

  6. Barlow DH . Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic. The Guilford Press: New York, 1988; 105–138.

    Google Scholar 

  7. Klein DF . False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry 1993; 50: 306–317.

    Article  CAS  PubMed  Google Scholar 

  8. Gorman JM, Kent JM, Sullivan GM, Coplan JD . Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000; 157: 493–505.

    Article  CAS  PubMed  Google Scholar 

  9. Hettema JM, Neale MC, Kendler KS . A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001; 158: 1568–1578.

    Article  CAS  PubMed  Google Scholar 

  10. Middeldorp CM, Hottenga JJ, Slagboom PE, Sullivan PF, de Geus EJ, Posthuma D et al. Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype. Mol Psychiatry 2008; 13: 84–89.

    Article  CAS  PubMed  Google Scholar 

  11. Smoller JW, Gardner-Schuster E, Covino J . The genetic basis of panic and phobic anxiety disorders. Am J Med Genet C Semin Med Genet 2008; 148: 118–126.

    Article  Google Scholar 

  12. Maron E, Hettema JH, Shlik J . The genetics of human anxiety disorders. In: Huston JP, Blanchard RJ, Blanchard DC, Griebel G, Nutt D (eds). Handbook of Anxiety and Fear,, vol. 17. Elsevier: Amsterdam, 2008 pp 475–510.

    Chapter  Google Scholar 

  13. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S et al. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet 2001; 105: 548–557.

    Article  CAS  PubMed  Google Scholar 

  14. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R . Genomewide survey of panic disorder. Am J Med Genet 2001; 105: 105–109.

    Article  CAS  PubMed  Google Scholar 

  15. Keck ME, Kern N, Erhardt A, Unschuld PG, Ising M, Salyakina D et al. Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1196–1204.

    Article  PubMed  Google Scholar 

  16. Keck ME, Wigger A, Welt T, Müller MB, Gesing A, Reul JM et al. Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: implications for pathogenesis of affective disorders. Neuropsychopharmacology 2002; 26: 94–105.

    Article  CAS  PubMed  Google Scholar 

  17. Le Mellédo JM, Bradwejn J, Koszycki D, Bellavance F, Bichet D . Arginine-vasopressin and oxytocin response to cholecystokinin-tetrapeptide. Peptides 2001; 22: 1349–1357.

    Article  PubMed  Google Scholar 

  18. Koido K, Eller T, Kingo K, Kõks S, Traks T, Shlik J et al. IKBKE gene in the chromosomal region of interleukin 10 gene is possibly related to mood and anxiety disorders. J Psychiatr Res 2009; advance online publication, 26 September 2009.

  19. Leygraf A, Hohoff C, Freitag C, Willis-Owen SA, Krakowitzky P, Fritze J et al. Rgs 2 gene polymorphisms as modulators of anxiety in humans? J Neural Transm 2006; 113: 1921–1925.

    Article  CAS  PubMed  Google Scholar 

  20. Hohoff C, Neumann A, Domschke K, Jacob C, Maier W, Fritze J et al. Association analysis of Rgs7 variants with panic disorder. J Neural Transm 2008; 116: 1523–1528.

    Article  CAS  PubMed  Google Scholar 

  21. Koenen KC, Amstadter AB, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG et al. RGS2 and generalized anxiety disorder in an epidemiologic sample of hurricane-exposed adults. Depress Anxiety 2009; 26: 309–315.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Strug LJ, Suresh R, Fyer AJ, Talati A, Adams PB, Li W et al. Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry 2008; advance online publication, 29 July 2008.

  23. Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R et al. A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry 2006; 60: 388–401.

    Article  CAS  PubMed  Google Scholar 

  24. Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJ, Kendler KS et al. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 2006; 11: 752–762.

    Article  CAS  PubMed  Google Scholar 

  25. Thoeringer CK, Binder EB, Salyakina D, Erhardt A, Ising M, Unschuld PG et al. Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks. J Psychiatr Res 2007; 41: 579–584.

    Article  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA et al. Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy. Arch Gen Psychiatry 2001; 58: 556–561.

    Article  CAS  PubMed  Google Scholar 

  28. Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ . Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998; 55: 715–720.

    Article  CAS  PubMed  Google Scholar 

  29. Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC . Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography. Arch Gen Psychiatry 2008; 65: 1166–1175.

    Article  PubMed  Google Scholar 

  30. Hasler G, van der Veen JW, Geraci M, Shen J, Pine D, Drevets WC . Prefrontal cortical gamma-aminobutyric Acid levels in panic disorder determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2009; 65: 273–275.

    Article  CAS  PubMed  Google Scholar 

  31. Cameron OG, Huang GC, Nichols T, Koeppe RA, Minoshima S, Rose D et al. Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder. Arch Gen Psychiatry 2007; 64: 793–800.

    Article  CAS  PubMed  Google Scholar 

  32. Maron E, Nikopensius T, Kõks S, Altmäe S, Heinaste E, Vabrit K et al. Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr Genet 2005; 15: 17–24.

    Article  PubMed  Google Scholar 

  33. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Hattori E, Ebihara M, Yamada K, Ohba H, Shibuya H, Yoshikawa T . 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 2001; 6: 465–470.

    Article  CAS  PubMed  Google Scholar 

  36. Thoeringer CK, Ripke S, Unschuld PG, Lucae S, Ising M, Bettecken T et al. The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders. J Neural Transm 2009; 116: 649–657.

    Article  CAS  PubMed  Google Scholar 

  37. Kaabi B, Gelernter J, Woods SW, Goddard A, Page GP, Elston RC . Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. Am J Hum Genet 2006; 78: 543–553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Domschke K, Hohoff C, Jacob C, Maier W, Fritze J, Bandelow B et al. Chromosome 4q31-34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 510–516.

    Article  PubMed  Google Scholar 

  39. Sajdyk TJ, Schober DA, Gehlert DR . Neuropeptide Y receptor subtypes in the basolateral nucleus of the amygdala modulate anxiogenic responses in rats. Neuropharmacology 2002; 43: 1165–1172.

    Article  CAS  PubMed  Google Scholar 

  40. Sorensen G, Lindberg C, Wortwein G, Bolwig TG, Woldbye DP . Differential roles for neuropeptide Y Y1 and Y5 receptors in anxiety and sedation. J Neurosci Res 2004; 77: 723–729.

    Article  CAS  PubMed  Google Scholar 

  41. Miyasaka K, Yoshida Y, Matsushita S, Higuchi S, Shirakawa O, Shimokata H et al. Association of cholecystokinin-A receptor gene polymorphisms and panic disorder in Japanese. Am J Med Genet B Neuropsychiatr Genet 2004; 127B: 78–80.

    Article  PubMed  Google Scholar 

  42. Ise K, Akiyoshi J, Horinouchi Y, Tsutsumi T, Isogawa K, Nagayama H . Association between the CCK-A receptor gene and panic disorder. Am J Med Genet B Neuropsychiatr Genet 2003; 118B: 29–31.

    Article  PubMed  Google Scholar 

  43. Rothe C, Gutknecht L, Freitag C, Tauber R, Mössner R, Franke P et al. Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. Int J Neuropsychopharmacol 2004; 7: 189–192.

    Article  CAS  PubMed  Google Scholar 

  44. Huang YY, Battistuzzi C, Oquendo MA, Harkavy-Friedman J, Greenhill L, Zalsman G et al. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. Int J Neuropsychopharmacol 2004; 7: 441–451.

    Article  CAS  PubMed  Google Scholar 

  45. Hettema JM, An SS, van den Oord EJ, Neale MC, Kendler KS, Chen X . Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 661–666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Domschke K, Braun M, Ohrmann P, Suslow T, Kugel H, Bauer J et al. Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3T fMRI in panic disorder. Int J Neuropsychopharmacol 2006; 9: 349–355.

    Article  CAS  PubMed  Google Scholar 

  47. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788–8799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Parsey RV, Olvet DM, Oquendo MA, Huang YY, Ogden RT, Mann JJ . Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 2006; 31: 1745–1749.

    Article  CAS  PubMed  Google Scholar 

  49. David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R et al. A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 2005; 25: 2586–2590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA et al. Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 2004; 24: 589–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nash JR, Sargent PA, Rabiner EA, Hood SD, Argyropoulos SV, Potokar JP et al. Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study. Br J Psychiatry 2008; 193: 229–234.

    Article  PubMed  Google Scholar 

  52. Yevtushenko OO, Oros MM, Reynolds GP . Early response to selective serotonin reuptake inhibitors in panic disorder is associated with a functional 5-HT1A receptor gene polymorphism. J Affect Disord 2009; advance online publication, 30 September 2009.

  53. Donner J, Pirkola S, Silander K, Kananen L, Terwilliger JD, Lönnqvist J et al. An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biol Psychiatry 2008; 64: 672–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Politi P, Minoretti P, Falcone C, Martinelli V, Emanuele E . Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder. Neurosci Lett 2006; 396: 163–166.

    Article  CAS  PubMed  Google Scholar 

  55. Hovatta I, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 2005; 438: 662–666.

    Article  CAS  PubMed  Google Scholar 

  56. Logue MW, Vieland VJ, Goedken RJ, Crowe RR . Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7. Am J Med Genet B Neuropsychiatr Genet 2003; 121: 95–99.

    Article  Google Scholar 

  57. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA et al. Results of a genome-wide genetic screen for panic disorder. Am J Med Genet 1998; 81: 139–147.

    Article  CAS  PubMed  Google Scholar 

  58. Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S et al. Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1444–1448.

    Article  CAS  PubMed  Google Scholar 

  59. Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E et al. Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. Am J Med Genet B Neuropsychiatr Genet 2008; 150B: 808–816.

    Article  Google Scholar 

  60. Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H et al. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet 2003; 72: 1221–1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang AG, Dahl HA, Vang M, Als TD, Ewald H, Kruse TA et al. Genetics of panic disorder on the Faroe Islands: a replication study of chromosome 9 and panic disorder. Psychiatr Genet 2006; 16: 99–104.

    Article  PubMed  Google Scholar 

  62. Smoller JW, Acierno Jr JS, Rosenbaum JF, Biederman J, Pollack MH, Meminger S et al. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 2001; 105: 195–206.

    Article  CAS  PubMed  Google Scholar 

  63. O’Brien JS, Carson GS, Seo HC, Hiraiwa M, Kishimoto Y . Identification of prosaposin as a neurotrophic factor. Proc Natl Acad Sci USA 1994; 91: 9593–9596.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hiraiwa M, Liu J, Lu AG, Wang CY, Misasi R, Yamauchi T et al. Regulation of gene expression in response to brain injury: Enhanced expression and alternative splicing of rat prosaposin (SGP-1) mRNA in injured brain. J Neurotrauma 2003; 20: 755–765.

    Article  PubMed  Google Scholar 

  65. Domschke K, Kuhlenbäumer G, Schirmacher A, Lorenzi C, Armengol L, DiBella D et al. Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2003; 117B: 70–78.

    Article  CAS  PubMed  Google Scholar 

  66. Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE et al. Investigation of polymorphisms in the CREM gene in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2004; 126B: 111–115.

    Article  PubMed  Google Scholar 

  67. Hösing VG, Schirmacher A, Kuhlenbäumer G, Freitag C, Sand P, Schlesiger C et al. Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder. J Neural Transm Suppl 2004; 68: 147–156.

    Article  Google Scholar 

  68. Hamilton SP, Slager SL, Helleby L, Heiman GA, Klein DF, Hodge SE et al. No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder. Mol Psychiatry 2001; 6: 59–65.

    Article  CAS  PubMed  Google Scholar 

  69. Unschuld PG, Ising M, Erhardt A, Lucae S, Kohli M, Kloiber S et al. Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder. J Affect Disord 2008; 105: 177–184.

    Article  CAS  PubMed  Google Scholar 

  70. Ho HP, Westberg L, Annerbrink K, Olsson M, Melke J, Nilsson S et al. Association between a functional polymorphism in the progesterone receptor gene and panic disorder in women. Psychoneuroendocrinology 2004; 29: 1138–1141.

    Article  CAS  PubMed  Google Scholar 

  71. Erhardt A, Lucae S, Unschuld PG, Ising M, Kern N, Salyakina D et al. Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders. J Affect Disord 2007; 101: 159–168.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG . Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 2004; 305: 217.

    Article  CAS  PubMed  Google Scholar 

  73. Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P et al. The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder. J Psychopharmacol 2006; 20: 547–552.

    Article  PubMed  Google Scholar 

  74. Kim YK, Lee HJ, Yang JC, Hwang JA, Yoon HK . A tryptophan hydroxylase 2 gene polymorphism is associated with panic disorder. Behav Genet 2009; 39: 170–175.

    Article  PubMed  Google Scholar 

  75. Maron E, Tõru I, Must A, Tasa G, Toover E, Vasar V et al. Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder. Neurosci Lett 2007; 411: 180–184.

    Article  CAS  PubMed  Google Scholar 

  76. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de LA, Hodge SE et al. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA 2003; 100: 2550–2555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Weissman MM, Fyer AJ, Haghighi F, Heiman G, Deng Z, Hen R et al. Potential panic disorder syndrome: clinical and genetic linkage evidence. Am J Med Genet 2000; 96: 24–35.

    Article  CAS  PubMed  Google Scholar 

  78. Talati A, Ponniah K, Strug LJ, Hodge SE, Fyer AJ, Weissman MM . Panic disorder, social anxiety disorder, and a possible medical syndrome previously linked to chromosome 13. Biol Psychiatry 2008; 63: 594–601.

    Article  CAS  PubMed  Google Scholar 

  79. Schumacher J, Abou Jamra R, Becker T, Klopp N, Franke P, Jacob C et al. Investigation of the DAOA/G30 locus in panic disorder. Mol Psychiatry 2005; 10: 428–429.

    Article  CAS  PubMed  Google Scholar 

  80. Rietschel M, Beckmann L, Strohmaier J, Georgi A, Karpushova A, Schirmbeck F et al. G72 and its association with major depression and neuroticism in large population-based groups from Germany. Am J Psychiatry 2008; 165: 753–762.

    Article  PubMed  Google Scholar 

  81. Chen YS, Akula N, Detera-Wadleigh SD, Schulze TG, Thomas J, Potash JB et al. Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33. Mol Psychiatry 2004; 9: 87–92.

    Article  CAS  PubMed  Google Scholar 

  82. Detera-Wadleigh SD, McMahon FJ . G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 2006; 60: 106–114.

    Article  CAS  PubMed  Google Scholar 

  83. Inada Y, Yoneda H, Koh J, Sakai J, Himei A, Kinoshita Y et al. Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Psychiatry Res 2003; 118: 25–31.

    Article  CAS  PubMed  Google Scholar 

  84. Rothe C, Koszycki D, Bradwejn J, King N, De Luca V, Shaikh S et al. Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany. Neurosci Lett 2004; 363: 276–279.

    Article  CAS  PubMed  Google Scholar 

  85. Fehr C, Schleicher A, Szegedi A, Anghelescu I, Klawe C, Hiemke C et al. Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 965–982.

    Article  CAS  PubMed  Google Scholar 

  86. Unschuld PG, Ising M, Erhardt A, Lucae S, Kloiber S, Kohli M et al. Polymorphisms in the serotonin receptor gene HTR2A are associated with quantitative traits in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 424–429.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  88. de Paula Soares V, Zangrossi Jr H . Stimulation of 5-HT1A or 5-HT2A receptors in the ventrolateral periaqueductal gray causes anxiolytic-, but not panicolytic-like effect in rats. Behav Brain Res 2009; 197: 178–185.

    Article  CAS  PubMed  Google Scholar 

  89. de Bortoli VC, Nogueira RL, Zangrossi Jr H . Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT(1A) and 5-HT (2A) receptors in the rat dorsal periaqueductal gray. Psychopharmacology (Berl) 2008; 198: 341–349.

    Article  CAS  Google Scholar 

  90. Gelernter J, Page GP, Bonvicini K, Woods SW, Pauls DL, Kruger S . A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol Psychiatry 2003; 8: 71–82.

    Article  CAS  PubMed  Google Scholar 

  91. Tang M, Cui M, Dong Q, Ren HM, Xiao BG, Luo BY et al. The bradykinin B2 receptor mediates hypoxia/reoxygenation induced neuronal cell apoptosis through the ERK1/2 pathway. Neurosci Lett 2009; 450: 40–44.

    Article  CAS  PubMed  Google Scholar 

  92. Gratacòs M, Nadal M, Martín-Santos R, Pujana MA, Gago J, Peral B et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 2001; 106: 367–379.

    Article  PubMed  Google Scholar 

  93. Schumacher J, Otte AC, Becker T, Sun Y, Wienker TF, Wirth B et al. No evidence for DUP25 in patients with panic disorder using a quantitative real-time PCR approach. Hum Genet 2003; 114: 115–117.

    Article  CAS  PubMed  Google Scholar 

  94. Tabiner M, Youings S, Dennis N, Baldwin D, Buis C, Mayers A et al. Failure to find DUP25 in patients with anxiety disorders, in control individuals, or in previously reported positive control cell lines. Am J Hum Genet 2003; 72: 535–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Henrichsen CN, Delorme R, Boucherie M, Marelli D, Baud P, Bellivier F et al. No association between DUP25 and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2004; 128B: 80–83.

    Article  PubMed  Google Scholar 

  96. Armengol L, Gratacòs M, Pujana MA, Ribasés M, Martín-Santos R, Estivill X . 5′ UTR-region SNP in the NTRK3 gene is associated with panic disorder. Mol Psychiatry 2002; 7: 928–930.

    Article  CAS  PubMed  Google Scholar 

  97. Gelernter J, Page GP, Stein MB, Woods SW . Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus. Am J Psychiatry 2004; 161: 59–66.

    Article  PubMed  Google Scholar 

  98. Maron E, Lang A, Tasa G, Liivlaid L, Tõru I, Must A et al. Associations between serotonin-related gene polymorphisms and panic disorder. Int J Neuropsychopharmacol 2005; 8: 261–266.

    Article  CAS  PubMed  Google Scholar 

  99. Blaya C, Salum GA, Lima MS, Leistner-Segal S, Manfro GG . Lack of association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder: a systematic review and meta-analysis. Behav Brain Funct 2007; 3: 41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Perna G, Favaron E, Di Bella D, Bussi R, Bellodi L . Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology 2005; 30: 2230–2235.

    Article  CAS  PubMed  Google Scholar 

  101. Kim W, Choi YH, Yoon KS, Cho DY, Pae CU, Woo JM . 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 2006; 30: 1413–1418.

    Article  CAS  PubMed  Google Scholar 

  102. Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 2003; 6: 1100–1107.

    Article  CAS  PubMed  Google Scholar 

  103. Okuyama S, Sakagawa T, Chaki S, Imagawa Y, Ichiki T, Inagami T . Anxiety-like behavior in mice lacking the angiotensin II type-2 receptor. Brain Res 1999; 821: 150–159.

    Article  CAS  PubMed  Google Scholar 

  104. Shekhar A, Johnson PL, Sajdyk TJ, Fitz SD, Keim SR, Kelley PE et al. Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci 2006; 26: 9205–9215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Olsson M, Annerbrink K, Westberg L, Melke J, Baghaei F, Rosmond R et al. Angiotensin-related genes in patients with panic disorder. Am J Med Genet B Neuropsychiatr Genet 2004; 127B: 81–84.

    Article  PubMed  Google Scholar 

  106. Bandelow B, Saleh K, Pauls J, Domschke K, Wedekind D, Falkai P . Insertion/deletion polymorphism in the gene for angiotensin converting enzyme (ACE) in panic disorder: A gender-specific effect? World J Biol Psychiatry 2007; 10: 1–5.

    Article  Google Scholar 

  107. Erhardt A, Lucae S, Kern N, Unschuld PG, Ising M, Lieb R et al. Association of polymorphisms in the angiotensin-converting enzyme gene with syndromal panic attacks. Mol Psychiatry 2008; 13: 242–243.

    Article  CAS  PubMed  Google Scholar 

  108. Shimizu E, Hashimoto K, Kobayashi K, Mitsumori M, Ohgake S, Koizumi H et al. Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans. Neurosci Lett 2004; 363: 81–83.

    Article  CAS  PubMed  Google Scholar 

  109. MacKinnon DF, Xu J, McMahon FJ, Simpson SG, Stine OC, McInnis MG et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry 1998; 155: 829–831.

    Article  CAS  PubMed  Google Scholar 

  110. Hodges LM, Weissman MM, Haghighi F, Costa R, Bravo O, Evgrafov O et al. Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 65–73.

    Article  CAS  PubMed  Google Scholar 

  111. Uhde TW, Tancer ME, Rubinow DR, Roscow DB, Boulenger JP, Vittone B et al. Evidence for hypothalamo-growth hormone dysfunction in panic disorder: profile of growth hormone (GH) responses to clonidine, yohimbine, caffeine, glucose, GRF and TRH in panic disorder patients versus healthy volunteers. Neuropsychopharmacology 1992; 6: 101–118.

    CAS  PubMed  Google Scholar 

  112. Tancer ME, Stein MB, Black B, Uhde TW . Blunted growth hormone responses to growth hormone-releasing factor and to clonidine in panic disorder. Am J Psychiatry 1993; 150: 336–337.

    Article  CAS  PubMed  Google Scholar 

  113. Nakamura M, Ueno S, Sano A, Tanabe H . Polymorphisms of the human homologue of the Drosophila white gene are associated with mood and panic disorders. Mol Psychiatry 1999; 4: 155–162.

    Article  CAS  PubMed  Google Scholar 

  114. Boulenger JP, Marangos PJ, Patel J, Uhde TW, Post RM . Central adenosine receptors: possible involvement in the chronic effects of caffeine. Psychopharmacol Bull 1984; 20: 431–435.

    CAS  PubMed  Google Scholar 

  115. Charney DS, Heninger GR Jatlow PI . Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 1985; 42: 233–243.

    Article  CAS  PubMed  Google Scholar 

  116. Deckert J, Nöthen MM, Franke P, Delmo C, Fritze J, Knapp M et al. Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 1998; 3: 81–85.

    Article  CAS  PubMed  Google Scholar 

  117. Hamilton SP, Slager SL, De Leon AB, Heiman GA, Klein DF, Hodge SE et al. Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology 2004; 29: 558–565.

    Article  CAS  PubMed  Google Scholar 

  118. Yamada K, Hattori E, Shimizu M, Sugaya A, Shibuya H, Yoshikawa T . Association studies of the cholecystokinin B receptor and A2a adenosine receptor genes in panic disorder. J Neural Transm 2001; 108: 837–848.

    Article  CAS  PubMed  Google Scholar 

  119. Lam P, Hong CJ, Tsai SJ . Association study of A2a adenosine receptor genetic polymorphism in panic disorder. Neurosci Lett 2005; 378: 98–101.

    Article  CAS  PubMed  Google Scholar 

  120. Ohara K, Nagai M, Suzuki Y, Ochiai M, Ohara K . No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res 1998; 80: 145–148.

    Article  CAS  PubMed  Google Scholar 

  121. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF et al. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 2002; 51: 591–601.

    Article  CAS  PubMed  Google Scholar 

  122. Woo JM, Yoon KS, Yu BH . Catechol O-methyltransferase genetic polymorphism in panic disorder. Am J Psychiatry 2002; 159: 1785–1787.

    Article  PubMed  Google Scholar 

  123. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH . The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 2004; 38: 365–370.

    PubMed  Google Scholar 

  124. Domschke K, Freitag CM, Kuhlenbäumer G, Schirmacher A, Sand P, Nyhuis P et al. Association of the functional V158 M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 2004; 7: 183–188.

    Article  CAS  PubMed  Google Scholar 

  125. Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepieñ G, Grzywacz A et al. Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res 2004; 128: 21–26.

    Article  CAS  PubMed  Google Scholar 

  126. Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, Tharmalingam S et al. Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology 2006; 31: 2237–2242.

    Article  CAS  PubMed  Google Scholar 

  127. Hettema JM, An SS, Bukszar J, van den Oord EJ, Neale MC, Kendler KS et al. Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes. Biol Psychiatry 2008; 64: 302–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Domschke K, Deckert J, O’donovan MC, Glatt SJ . Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 667–673.

    Article  CAS  PubMed  Google Scholar 

  129. Domschke K, Ohrmann P, Braun M, Suslow T, Bauer J, Hohoff C et al. Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res 2008; 163: 13–20.

    Article  CAS  PubMed  Google Scholar 

  130. Nakamura K, Yamada K, Iwayama Y, Toyota T, Furukawa A, Takimoto T et al. Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 222–226.

    Article  CAS  PubMed  Google Scholar 

  131. Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D 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  PubMed  Google Scholar 

  132. Hamilton SP, Slager SL, Heiman GA, Haghighi F, Klein DF, Hodge SE et al. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder. Mol Psychiatry 2000; 5: 465–466.

    Article  CAS  PubMed  Google Scholar 

  133. Shifman S, Bronstein M, Sternfeld M, Pisanté-Shalom A, Lev-Lehman E, Weizman A et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–1302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, Muir W et al. Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry 2005; 10: 598–605.

    Article  CAS  PubMed  Google Scholar 

  135. Kirov G, Murphy KC, Arranz MJ, Jones I, McCandles F, Kunugi H et al. Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 1998; 3: 342–345.

    Article  CAS  PubMed  Google Scholar 

  136. McGuffin P, Knight J, Breen G, Brewster S, Boyd PR, Craddock N et al. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum Mol Genet 2005; 14: 3337–3345.

    Article  CAS  PubMed  Google Scholar 

  137. Logue MW, Durner M, Heiman GA, Hodge SE, Hamilton SP, Knowles JA et al. A linkage search for joint panic disorder/bipolar genes. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 1139–1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sullivan PF . Spurious genetic associations. Biol Psychiatry 2007; 61: 1121–1126.

    Article  CAS  PubMed  Google Scholar 

  139. Hattersley AT, McCarthy MI . What makes a good genetic association study? Lancet 2005; 366: 1315–1323.

    Article  PubMed  Google Scholar 

  140. Mill J, Petronis A . Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry 2007; 12: 799–814.

    Article  CAS  PubMed  Google Scholar 

  141. Polesskaya OO, Aston C, Sokolov BP . Allele C-specific methylation of the 5-HT2A receptor gene: evidence for correlation with its expression and expression of DNA methylase DNMT1. J Neurosci Res 2006; 83: 362–373.

    Article  CAS  PubMed  Google Scholar 

  142. Dempster EL, Mill J, Craig IW, Collier DA . The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC Med Genet 2006; 7: 10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Potkin SG, Turner JA, Fallon JA, Lakatos A, Keator DB, Guffanti G et al. Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia. Mol Psychiatry 2009; 14: 416–428.

    Article  CAS  PubMed  Google Scholar 

  144. O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Molecular Genetics of Schizophrenia Collaboration. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

    Article  CAS  PubMed  Google Scholar 

  145. O’Donovan MC, Norton N, Williams H, Peirce T, Moskvina V, Nikolov I et al. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2. Mol Psychiatry 2009; 14: 30–36.

    Article  CAS  PubMed  Google Scholar 

  146. Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E et al. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009; 14: 252–260.

    Article  CAS  PubMed  Google Scholar 

  147. Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K et al. Whole-genome association study of bipolar disorder. Mol Psychiatry 2008; 13: 558–569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Baum AE, Hamshere M, Green E, Cichon S, Rietschel M, Noethen MM et al. Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement. Mol Psychiatry 2008; 13: 466–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  CAS  Google Scholar 

  151. Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ et al. Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry 2008; advance online publication, 23 December 2008.

  152. Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T et al. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 2009; 14: 359–375.

    Article  CAS  PubMed  Google Scholar 

  153. Shifman S, Bhomra A, Smiley S, Wray NR, James MR, Martin NG et al. A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry 2008; 13: 302–312.

    Article  CAS  PubMed  Google Scholar 

  154. van den Oord EJ, Kuo PH, Hartmann AM, Webb BT, Möller HJ, Hettema JM et al. Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Arch Gen Psychiatry 2008; 65: 1062–1071.

    Article  PubMed  Google Scholar 

  155. Lavedan C, Licamele L, Volpi S, Hamilton J, Heaton C, Mack K et al. Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol Psychiatry 2009; 14: 804–819.

    Article  CAS  PubMed  Google Scholar 

  156. Volpi S, Heaton C, Mack K, Hamilton JB, Lannan R, Wolfgang CD et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol Psychiatry 2008; 14: 1024–1031.

    Article  CAS  PubMed  Google Scholar 

  157. Burmeister M, McInnis MG, Zöllner S . Psychiatric genetics: progress amid controversy. Nat Rev Genet 2008; 9: 527–540.

    Article  CAS  PubMed  Google Scholar 

  158. Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K et al. Genome-wide association study of panic disorder in the Japanese population. J Hum Genet 2009; 54: 122–126.

    Article  CAS  PubMed  Google Scholar 

  159. Askland K, Read C, Moore J . Pathways-based analyses of whole-genome association study data in bipolar disorder reveal genes mediating ion channel activity and synaptic neurotransmission. Hum Genet 2009; 125: 63–79.

    Article  CAS  PubMed  Google Scholar 

  160. Potkin SG, Turner JA, Fallon JA, Lakatos A, Keator DB, Guffanti G et al. Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia. Mol Psychiatry 2009; 14: 416–428.

    Article  CAS  PubMed  Google Scholar 

  161. Potkin SG, Turner JA, Guffanti G, Lakatos A, Fallon JH, Nguyen DD et al. A genome-wide association study of schizophrenia using brain activation as a quantitative phenotype. Schizophr Bull 2009; 35: 96–108.

    Article  PubMed  Google Scholar 

  162. Alsene K, Deckert J, Sand P, de Wit H . Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 2003; 28: 1694–1702.

    Article  CAS  PubMed  Google Scholar 

  163. Schmidt NB, Storey J, Greenberg BD, Santiago HT, Li Q, Murphy DL . Evaluating gene x psychological risk factor effects in the pathogenesis of anxiety: a new model approach. J Abnorm Psychol 2000; 109: 308–320.

    Article  CAS  PubMed  Google Scholar 

  164. Perna G, Di Bella D, Favaron E, Cucchi M, Liperi L, Bellodi L . Lack of relationship between CO2 reactivity and serotonin transporter gene regulatory region polymorphism in panic disorder. Am J Med Genet B Neuropsychiatr Genet 2004; 129: 41–43.

    Article  Google Scholar 

  165. Maron E, Tasa G, Tõru I, Lang A, Vasar V, Shlik J . Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers. World J Biol Psychiatry 2004; 5: 149–154.

    Article  PubMed  Google Scholar 

  166. Maron E, Tõru I, Tasa G, Must A, Toover E, Lang A et al. Association testing of panic disorder candidate genes using CCK-4 challenge in healthy volunteers. Neurosci Lett 2008; 446: 88–92.

    Article  CAS  PubMed  Google Scholar 

  167. Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA . The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006; 147: 126–132.

    Article  CAS  PubMed  Google Scholar 

  168. Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N, Shalev AY . Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry 2005; 10: 500–513.

    Article  CAS  PubMed  Google Scholar 

  169. Zieker J, Zieker D, Jatzko A, Dietzsch J, Nieselt K, Schmitt A et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol Psychiatry 2007; 12: 116–118.

    Article  CAS  PubMed  Google Scholar 

  170. Philibert RA, Crowe R, Ryu GY, Yoon JG, Secrest D, Sandhu H et al. Transcriptional profiling of lymphoblast lines from subjects with panic disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 674–682.

    Article  CAS  PubMed  Google Scholar 

  171. Maron E, Kallassalu K, Tammiste A, Kolde R, Vilo J, Tõru I et al. Peripheral gene expression profiling of CCK-4-induced panic in healthy subjects. Am J Med Genet B Neuropsychiatr Genet 2008; advance online publication, 2 December 2008.

  172. Bajwa WK, Asnis GM, Sanderson WC, Irfan A, van Praag HM . High cholesterol levels in patients with panic disorder. Am J Psychiatry 1992; 149: 376–378.

    Article  CAS  PubMed  Google Scholar 

  173. A∂argün MY, Kara H, Algün E, Sekeroglu R, Tarakçio∂lu M . High cholesterol levels in patients with sleep panic. Biol Psychiatry 1996; 40: 1064–1065.

    Article  Google Scholar 

  174. Perez-Parada J, Jhangri GS, Lara N, Chrapko W, Castillo Abadia Mdel P, Gil L et al. Delayed increase in LDL cholesterol following pentagastrin-induced panic attacks. Psychopharmacology (Berl) 2007; 193: 333–340.

    Article  CAS  Google Scholar 

  175. Le Hellard S, Mühleisen TW, Djurovic S, Fernø J, Ouriaghi Z, Mattheisen M et al. Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples. Mol Psychiatry 2008; advance online publication, 21 October 2008.

  176. Simon NM, Fischmann D . The implications of medical and psychiatric comorbidity with panic disorder. J Clin Psychiatry 2005; 66: 8–15.

    PubMed  Google Scholar 

  177. Zaubler TS, Katon W . Panic disorder and medical comorbidity: a review of the medical and psychiatric literature. Bull Menninger Clin 1996; 60: 12–38.

    Google Scholar 

  178. Shioiri T, Kojima-Maruyama M, Hosoki T, Kitamura H, Tanaka A, Yoshizawa M et al. Dysfunctional baroreflex regulation of sympathetic nerve activity in remitted patients with panic disorder. A new methodological approach. Eur Arch Psychiatry Clin Neurosci 2005; 255: 293–298.

    Article  PubMed  Google Scholar 

  179. Lee IS, Kim KJ, Kang EH, Yu BH . beta-adrenoceptor affinity as a biological predictor of treatment response to paroxetine in patients with acute panic disorder. J Affect Disord 2008; 110: 156–160.

    Article  CAS  PubMed  Google Scholar 

  180. Yeragani VK, Chokka P, Tancer M, Sivaraju A, Bar KJ . Increased beat-to-beat ‘R’ amplitude variability in patients with panic disorder. Int J Cardiol 2008; advance online publication, 20 December 2008.

  181. Davies SJ, Jackson PR, Lewis G, Hood SD, Nutt DJ, Potokar JP . Is the association of hypertension and panic disorder explained by clustering of autonomic panic symptoms in hypertensive patients? J Affect Disord 2008; 111: 344–350.

    Article  PubMed  Google Scholar 

  182. Nardi AE, Freire RC, Zin WA . Panic disorder and control of breathing. Respir Physiol Neurobiol 2009; 167: 133–143.

    Article  PubMed  Google Scholar 

  183. Hall IP, Blakey JD, Al Balushi KA, Wheatley A, Sayers I, Pembrey ME et al. Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet 2006; 368: 771–779.

    Article  CAS  PubMed  Google Scholar 

  184. Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M . Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 2007; 370: 2118–2225.

    Article  CAS  PubMed  Google Scholar 

  185. Taylor S . Anxiety sensitivity: theoretical perspectives and recent findings. Behav Res Ther 1995; 33: 243–258.

    Article  CAS  PubMed  Google Scholar 

  186. Schmidt NB, Richey JA, Cromer KR, Buckner JD . Discomfort intolerance: evaluation of a potential risk factor for anxiety psychopathology. Behav Ther 2007; 38: 247–255.

    Article  PubMed  Google Scholar 

  187. Bakker A, van Dyck R, Spinhoven P, van Balkom AJ . Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder. J Clin Psychiatry 1999; 60: 831–838.

    Article  CAS  PubMed  Google Scholar 

  188. Black DW, Wesner R, Bowers W, Gabel J . A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50: 44–50.

    Article  CAS  PubMed  Google Scholar 

  189. van Apeldoorn FJ, van Hout WJ, Mersch PP, Huisman M, Slaap BR, Hale III WW et al. Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia. Acta Psychiatr Scand 2008; 117: 260–270.

    Article  CAS  PubMed  Google Scholar 

  190. Coplan JD, Lydiard RB . Brain circuits in panic disorder. Biol Psychiatry 1998; 44: 1264–1276.

    Article  CAS  PubMed  Google Scholar 

  191. Deakin JFW, Graeff FG . 5-HT and mechanisms of defence. J Psychopharmacol 1991; 5: 305–315.

    Article  CAS  PubMed  Google Scholar 

  192. Graeff FG, Del-Ben CM . Neurobiology of panic disorder: from animal models to brain neuroimaging. Neurosci Biobehav Rev 2008; 32: 1326–1335.

    Article  PubMed  Google Scholar 

  193. Bandler R, Carrive P . Integrated defence reaction elicited by excitatory amino acid microinjection in the midbrain periaqueductal grey region of the unrestrained cat. Brain Res 1988; 439: 95–106.

    Article  CAS  PubMed  Google Scholar 

  194. Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A . Neural pathways underlying lactate-induced panic. Neuropsychopharmacology 2008; 33: 2093–2107.

    Article  CAS  PubMed  Google Scholar 

  195. Enoch MA, Waheed JF, Harris CR, Albaugh B, Goldman D . COMT Val158Met and cognition: main effects and interaction with educational attainment. Genes Brain Behav 2009; 8: 36–42.

    Article  PubMed  Google Scholar 

  196. Honea R, Verchinski BA, Pezawas L, Kolachana BS, Callicott JH, Mattay VS et al. Impact of interacting functional variants in COMT on regional gray matter volume in human brain. Neuroimage 2009; 45: 44–51.

    Article  PubMed  Google Scholar 

  197. Ham BJ, Lee MS, Lee YM, Kim MK, Choi MJ, Oh KS et al. Association between the catechol O-methyltransferase Val108/158Met polymorphism and alexithymia. Neuropsychobiology 2005; 52: 151–154.

    Article  CAS  PubMed  Google Scholar 

  198. Goghari VM, Sponheim SR . Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. Schizophr Res 2008; 103: 186–191.

    Article  PubMed  Google Scholar 

  199. Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Rogelj B . Brain-specific small nucleolar RNAs. J Mol Neurosci 2006; 28: 103–109.

    Article  CAS  PubMed  Google Scholar 

  201. Lee YJ, Hohoff C, Domschke K, Sand P, Kuhlenbäumer G, Schirmacher A et al. Norepinephrine transporter (NET) promoter and 5′-UTR polymorphisms: association analysis in panic disorder. Neurosci Lett 2005; 377: 40–43.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the Estonian Scientific Foundation Grant 7034 (EM) and the University of Ottawa Mental Health Research Fund (JS). We thank Professor David J Nutt from the Imperial College London, UK, for a helpful critical review of a draft of this manuscript and Professor Andres Metspalu from the University of Tartu, Estonia, for fruitful collaboration in genetic studies.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Tartu, Tartu, Estonia

    E Maron

  2. Estonian Genome Project, University of Tartu, Tartu, Estonia

    E Maron

  3. Department of Neuropsychopharmacology and Molecular Imaging, Imperial College London, London, UK

    E Maron

  4. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    J M Hettema

  5. Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada

    J Shlik

  6. Anxiety Disorders Program, Royal Ottawa Mental Health Centre, Ottawa, ON, Canada

    J Shlik

Authors
  1. E Maron
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Hettema
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Shlik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Maron.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maron, E., Hettema, J. & Shlik, J. Advances in molecular genetics of panic disorder. Mol Psychiatry 15, 681–701 (2010). https://doi.org/10.1038/mp.2009.145

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.145

Keywords

This article is cited by

Search

Advanced search

Quick links