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Panic disorders: The role of genetics and epigenetics

Department of Psychiatry, Korea University Ansan Hospital, Ansan, Republic of Korea

Panic disorder is characterized by symptoms with abrupt surges of fear with palpitations, sweating, trembling, heat sensations. Considering its disease burden on each individual and on society, understanding its etiology is important. Though no one specific etiology has been known, like other psychiatric disorders, multiple factors such as genetic, environmental, neurobiological, psychopathological factors have been suggested. In this article, we reviewed currently known etiologies and related study results, regarding especially genetic and epigenetic aspects of the panic disorder. Early studies, including twin studies, family studies, adoption studies suggested highly familial trait of panic disorder. Linkage studies, either, found panic disorder is not a single gene disorder but confirmed existence of multiple related genes. Chromosome and candidate gene studies found few related genes, NPY, ADORA2A, COMT, IKBKE. Newer method, genome-wide association studies (GWAS) have been searching for newer genes. No genome-wide significant genes, however, were detected, confirming previously known candidate genes, NPY5R on 4q31.3-32, BDKRB2 on 14q32, instead. Epigenetic modification has also been studied on many different psychiatric disorders. Monoamine oxidase A (MAOA) hypomethylation, taken together with negative life events, showed relation with panic disorder. Glutamate decarbodylases 1 (GAD1) hypomethylation was also specific on panic disorder patients. Relation with noradrenaline transporter (NET) gene SLC6a2 promoter methylation has also been studied. In conclusion, no specific gene or epigenetic pattern can fully explain etiology of panic disorder. Few genes and epigenetic patterns, however, showed strong association with panic disorder compared to healthy controls. Considering its multivariable background, further studies with larger populations can confirm current results and clarify etiologies of panic disorder.
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References

1. Association AP (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). Am Psychiatr Assoc 57: 1546–1548.

2. Alonso J, Lepine JP (2007) Overview of key data from the European Study of the Epidemiology of Mental Disorders (ESEMeD). J Clin Psychiatry 68: 3–9.    

3. Bourdon KH, Rae DS, Locke BZ, et al. (1991) Estimating the prevalence of mental disorders in US adults from the Epidemiologic Catchment Area Survey. Public H ealth Rep 107: 663–668.

4. Kessler RC, Petukhova M, Sampson NA, et al. (2012) Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J M ethods P sychiatr Res 21: 169–184.    

5. Bandelow B, Michaelis S (2015) Epidemiology of anxiety disorders in the 21st century. Dialogues C lin Neurosci 17: 327.

6. Wittchen HU, Jacobi F (2005) Size and burden of mental disorders in Europe-a critical review and appraisal of 27 studies. Eur N europsychopharmacol 15: 357–376.    

7. Carta MG, Moro MF, Aguglia E, et al. (2015) The attributable burden of panic disorder in the impairment of quality of life in a national survey in Italy. Int J So c Psychiatry 61: 693–699.    

8. Pitts FN, Mcclure JN (1967) Lactate metabolism in anxiety neurosis. New Eng l J Med 277: 1329–1336.    

9. Krystal JH, Deutsch DN, Charney DS (1996) The biological basis of panic disorder. J Clin Psychiatry 57: 23–31.

10. Uchida R, Del-Ben C, Santos A, et al. (2003) Decreased left temporal lobe volume of panic patients measured by magnetic resonance imaging. Braz J Med Biol Res 36: 925–929.    

11. Massana G, Gasto C, Junque C, et al. (2002) Reduced levels of creatine in the right medial temporal lobe region of panic disorder patients detected with 1 H magnetic resonance spectroscopy. Neuroimage 16: 836–842.    

12. Bremner JD, Innis RB, White T, et al. (2000) SPECT [I-123] iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 47: 96–106.    

13. Sibille E, Pavlides C, Benke D, et al. (2000) Genetic inactivation of the serotonin1A receptor in mice results in downregulation of major GABAA receptor α subunits, reduction of GABAA receptor binding, and benzodiazepine-resistant anxiety. J Neurosci 20: 2758–2765.    

14. Reiss S (1980) Pavlovian conditioning and human fear: An expectancy model. Behav Ther 11: 380–396.    

15. Watt MC, Stewart SH (2000) Anxiety sensitivity mediates the relationships between childhood learning experiences and elevated hypochondriacal concerns in young adulthood. J P sychosom Res 49: 107–118.

16. Schmidt NB, Lerew DR, Joiner TE (2000) Prospective evaluation of the etiology of anxiety sensitivity: Test of a scar model. Behav Res Ther 38: 1083–1095.    

17. Critchley HD, Wiens S, Rotshtein P, et al. (2004) Neural systems supporting interoceptive awareness. Nat Neurosci 7: 189–195.    

18. Regier DA, Narrow WE, Rae DS (1990) The epidemiology of anxiety disorders: The epidemiologic catchment area (ECA) experience. J Psychiatr Res 24: 3–14.

19. Alonso J, Angermeyer MC, Bernert S, et al. (2004) Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta P sychiatr S cand 109: 21–27.

20. Bandelow B, Domschke K (2015) Panic disorder, In: Stein DJ, Vythilingum B, Anxiety Disorder Gender, 2 Eds., Switzerland: Springer Int Publishing, 31–48.

21. Weissman MM (1993) Family genetic studies of panic disorder. J Psychiatr Res 27: 69–78.

22. Crowe RR, Noyes R, Pauls DL, et al. (1983) A family study of panic disorder. Arch Gen Psychiatry 40: 1065–1069.    

23. Smoller JW, Gardner-Schuster E, Covino J (2010) The genetic basis of panic and phobic anxiety disorders. Am J Med Genet Part C 148: 118–126.

24. Goldstein RB, Wickramaratne PJ, Horwath E, et al. (1997) Familial aggregation and phenomenology of Early-Onset (at or before age 20 years): Panic disorder. Arch Gen Psychiatry 54: 271–278.    

25. Kendler KS, Heath A, Martin NG, et al. (1986) Symptoms of anxiety and depression in a volunteer twin population: The etiologic role of genetic and environmental factors. Arch Gen Psychiatry 43: 213–221.    

26. Pauls DL, Bucher KD, Crowe RR, et al. (1980) A genetic study of panic disorder pedigrees. Am J human Genet. 32: 639–644.

27. Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233: 702–705.

28. Deckert J, Catalano M, Syagailo YV, et al. (1999) Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum M ol Genet 8: 621–624.

29. Domschke K, Reif A, Weber H, et al. (2011) Neuropeptide S receptor gene--converging evidence for a role in panic disorder. Mol Psychiatry 16: 938.    

30. Domschke K, Hohoff C, Jacob C, et al. (2008) Chromosome 4q31–34 panic disorder risk locus: Association of neuropeptide Y Y5 receptor variants. Am J Med Genet Part B 147: 510–516.

31. Weber H, Scholz CJ, Domschke K, et al. (2012) Gender differences in associations of glutamate decarboxylase 1 gene (GAD1) variants with panic disorder. PloS One 7: e37651.    

32. Maron E, Hettema J, Shlik J (2010) Advances in molecular genetics of panic disorder. Mol Psychiatry 15: 681–701.    

33. Keck ME, Kern N, Erhardt A, et al. (2008) Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am Ournal Med Genet Part B 147: 1196–1204.

34. Hohoff C, Neumann A, Domschke K, et al. (2009) Association analysis of Rgs7 variants with panic disorder. J N eural T ransm 116: 1523–1528.

35. Leygraf A, Hohoff C, Freitag C, et al. (2006) Rgs 2 gene polymorphisms as modulators of anxiety in humans? J Neural Transm 113: 1921.    

36. Koido K, Eller T, Kingo K, et al. (2010) Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes. J Psychiatr Res 44: 275–277.    

37. Kawai T, Akira S (2007) Signaling to NF-κB by Toll-like receptors. Trends M ol Med 13: 460–469.    

38. Pedrazzini T, Pralong F, Grouzmann E (2003) Neuropeptide Y: the universal soldier. Cell Mol Life Sci 60: 350–377.    

39. Boulenger JP, Jerabek I, Jolicoeur FB, et al. (1996) Elevated plasma levels of neuropeptide Y in patients with panic disorder. Am J Psychiatry 153: 114–116.    

40. Reinscheid RK, Xu YL (2005) Neuropeptide S as a novel arousal promoting peptide transmitter. FEBS J 272: 5689–5693.

41. Xu Y-L, Reinscheid RK, Huitron-Resendiz S, et al. (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43: 487–497.    

42. Okamura N, Hashimoto K, Iyo M, et al. (2007) 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 Neuro-Psychopharmacol Biol Psychiatry 31: 1444–1448.    

43. Thorgeirsson TE, Oskarsson H, Desnica N, et al. (2003) Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet 72: 1221–1230.    

44. Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61: 1179–1188.    

45. Vanderhaeghen JJ, Signeau J, Gepts W (1975) New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nat 257: 604–605.    

46. Huppi K, Siwarski D, Pisegna J, et al. (1995) Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse. Genomics 25: 727–729.    

47. Kato T, Wang ZW, Zoega T, et al. (1996) Missense mutation of the cholecystokinin B receptor gene: lack of association with panic disorder. Am J Med Genet Part A 67: 401.    

48. Schumacher J, Jamra RA, Becker T, et al. (2005) Investigation of the DAOA/G30 locus in panic disorder. Mol Psychiatry 10: 428–429.    

49. Maron E, Nikopensius T, Koks S, et al. (2005) Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr Genet 15: 17–24.    

50. Yoon HK, Yang JC, Lee HJ, et al. (2008) The association between serotonin-related gene polymorphisms and panic disorder. J A nxiety Disord 22: 1529–1534.    

51. Middeldorp CM, Hottenga JJ, Slagboom PE, et al. (2008) Linkage on chromosome 14 in a genomewide linkage study of a broad anxiety phenotype. Mol Psychiatry 13: 84.    

52. Holopainen IE, Metsähonkala E, Kokkonen H, et al. (2001) Decreased binding of [11C] flumazenil in Angelman syndrome patients with GABAA receptor β3 subunit deletions. Ann N eurol 49: 110.    

53. Strakhova MI, Harvey SC, Cook CM, et al. (2000) A single amino acid residue on the α5 subunit (Ile215) is essential for ligand selectivity at α5β3γ2 γ-aminobutyric acidA receptors. Mol P harmacol 58: 1434–1440.

54. Weissman MM, Fyer AJ, Haghighi F, et al. (2000) Potential panic disorder syndrome: clinical and genetic linkage evidence. Am J Med Genet Part A 96: 24–35.    

55. MacKinnon DF, Xu J, McMahon FJ, et al. (1998) Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry 155: 829–831.

56. Hamilton SP, Slager SL, Heiman GA, et al. (2002) Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 51: 591–601.    

57. Shulman R, Griffiths J, Diewold P (1978) Catechol-O-methyl transferase activity in patients with depressive illness and anxiety states. Br J Psychiatry 132: 133–138.    

58. Karayiorgou M, Sobin C, Blundell ML, et al. (1999) Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 45: 1178.    

59. Domschke K, Ohrmann P, Braun M, et al. (2008) Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res Neuroimaging 163: 13–20.    

60. Consortium TPG (2009) Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 166: 540–556.

61. Otowa T, Kawamura Y, Nishida N, et al. (2012) Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. Transl Psychiatry 2: e186.    

62. Gratacos M, Costas J, de Cid R, et al. (2009) 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 Part B 150: 808–816.

63. Erhardt A, Czibere L, Roeske D, et al. (2010) TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies. Mol Psychiatry 16: 647.

64. Gregersen N, Dahl HA, Buttenschon HN, et al. (2012) A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene. Eur J Hum Genet 20: 84.    

65. Otowa T, Yoshida E, Sugaya N, et al. (2009) Genome-wide association study of panic disorder in the Japanese population. J Hum Genet 54: 122–126.    

66. Schumacher J, Kristensen AS, Wendland JR, et al. (2001) The genetics of panic disorder. Curr Psychiatry Rep 3: 131–137.    

67. Onishchenko N, Karpova N, Sabri F, et al. (2008) Long‐lasting depression‐like behavior and epigenetic changes of BDNF gene expression induced by perinatal exposure to methylmercury. J N eurochem 106: 1378–1387.

68. Schroeder M, Hillemacher T, Bleich S, et al. (2012) The epigenetic code in depression: implications for treatment. Clin Pharmacol Ther 91: 310–314.    

69. Dalton VS, Kolshus E, Mcloughlin DM (2014) Epigenetics and depression: Return of the repressed. J A ffective D isord 155: 1–12.

70. Hervouet E, Vallette FM, Cartron PF (2009) Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenet 4: 487.    

71. Angelucci F, Croce N, Spalletta G, et al. (2011) Paroxetine rapidly modulates the expression of brain-derived neurotrophic factor mRNA and protein in a human glioblastoma-astrocytoma cell line. Pharmacol 87: 5–10.    

72. Qiu T, Zhou L, Zhu W, et al. (2013) Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future O ncol 9: 255–269.    

73. Shih J, Chen K (1999) MAO-A and-B gene knock-out mice exhibit distinctly different behavior. Neurobiol 7: 235–246.

74. Politi E, Balduzzi C, Bussi R, et al. (1999) Artificial neural networks: A study in clinical psychopharmacology. Psychiatry Res 87: 203.    

75. Domschke K, Tidow N, Kuithan H, et al. (2012) Monoamine oxidase A gene DNA hypomethylation-a risk factor for panic disorder? Int J Neuropsychopharmacol 15: 1217.    

76. Ziegler C, Richter J, Mahr M, et al. (2016) MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy. Transl Psychiatry 6: e773.    

77. Domschke K, Zwanzger P (2008) GABAergic and endocannabinoid dysfunction in anxiety-future therapeutic targets? Curr P harm D es 14: 3508–3517.

78. Hettema J, An S, Neale M, et al. (2006) Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 11: 752–762.    

79. Donner J, Sipila T, Ripatti S, et al. (2012) Support for involvement of glutamate decarboxylase 1 and neuropeptide Y in anxiety susceptibility. Am J Med Genet Part B 159: 316–327.

80. Bayles R, Baker EK, Jowett JB, et al. (2013) Methylation of the SLC6a2 gene promoter in major depression and panic disorder. PLoS One 8: e83223.    

81. Schartner C, Ziegler C, Schiele MA, et al. (2017) CRHR1 promoter hypomethylation: An epigenetic readout of panic disorder? Eur Neuropsychopharmacol 27: 360–371.    

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