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The CRF system, stress, depression and anxiety—insights from human genetic studies

Molecular Psychiatry volume 15, pages 574–588 (2010)Cite this article

Abstract

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF1 receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.

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References

  1. Vale W, Spiess J, Rivier C, Rivier J . Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981; 213: 1394–1397.

    Article  CAS  PubMed  Google Scholar 

  2. Britton DR, Koob GF, Rivier J, Vale W . Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty. Life Sci 1982; 31: 363–367.

    Article  CAS  PubMed  Google Scholar 

  3. Kalin NH . Behavioral effects of ovine corticotropin-releasing factor administered to rhesus monkeys. Fed Proc 1985; 44 (1 Part 2): 249–253.

    CAS  PubMed  Google Scholar 

  4. Kalin NH, Shelton SE, Kraemer GW, McKinney WT . Corticotropin-releasing factor administered intraventricularly to rhesus monkeys. Peptides 1983; 4: 217–220.

    Article  CAS  PubMed  Google Scholar 

  5. Koob GF, Bloom FE . Corticotropin-releasing factor and behavior. Fed Proc 1985; 44 (1 Part 2): 259–263.

    CAS  PubMed  Google Scholar 

  6. Koob GF, Thatcher-Britton K . Stimulant and anxiogenic effects of corticotropin releasing factor. Prog Clin Biol Res 1985; 192: 499–506.

    CAS  PubMed  Google Scholar 

  7. Sirinathsinghji DJ, Rees LH, Rivier J, Vale W . Corticotropin-releasing factor is a potent inhibitor of sexual receptivity in the female rat. Nature 1983; 305: 232–235.

    Article  CAS  PubMed  Google Scholar 

  8. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342–1344.

    Article  CAS  PubMed  Google Scholar 

  9. Nemeroff CB . The corticotropin-releasing factor (CRF) hypothesis of depression: new findings and new directions. Mol Psychiatry 1996; 1: 336–342.

    CAS  PubMed  Google Scholar 

  10. Reul JM, Holsboer F . Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2002; 2: 23–33.

    Article  CAS  PubMed  Google Scholar 

  11. Nemeroff CB, Vale WW . The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry 2005; 66 (Suppl 7): 5–13.

    CAS  PubMed  Google Scholar 

  12. Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM . International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. Pharmacol Rev 2003; 55: 21–26.

    Article  CAS  PubMed  Google Scholar 

  13. Boorse GC, Denver RJ . Widespread tissue distribution and diverse functions of corticotropin-releasing factor and related peptides. Gen Comp Endocrinol 2006; 146: 9–18.

    Article  CAS  PubMed  Google Scholar 

  14. Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K et al. Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. Proc Natl Acad Sci USA 1994; 91: 8777–8781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis KA, Rivier JE et al. Cloning and characterization of human urocortin. Endocrinology 1996; 137: 3896.

    Article  CAS  PubMed  Google Scholar 

  16. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci USA 2001; 98: 7570–7575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA 2001; 98: 2843–2848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995; 378: 287–292.

    Article  CAS  PubMed  Google Scholar 

  19. Bittencourt JC, Vaughan J, Arias C, Rissman RA, Vale WW, Sawchenko PE . Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol 1999; 415: 285–312.

    Article  CAS  PubMed  Google Scholar 

  20. Wong ML, al-Shekhlee A, Bongiorno PB, Esposito A, Khatri P, Sternberg EM et al. Localization of urocortin messenger RNA in rat brain and pituitary. Mol Psychiatry 1996; 1: 307–312.

    CAS  PubMed  Google Scholar 

  21. Kageyama K, Bradbury MJ, Zhao L, Blount AL, Vale WW . Urocortin messenger ribonucleic acid: tissue distribution in the rat and regulation in thymus by lipopolysaccharide and glucocorticoids. Endocrinology 1999; 140: 5651–5658.

    Article  CAS  PubMed  Google Scholar 

  22. Hashimoto K, Nishiyama M, Tanaka Y, Noguchi T, Asaba K, Hossein PN et al. Urocortins and corticotropin releasing factor type 2 receptors in the hypothalamus and the cardiovascular system. Peptides 2004; 25: 1711–1721.

    Article  CAS  PubMed  Google Scholar 

  23. Chalmers DT, Lovenberg TW, De Souza EB . Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J Neurosci 1995; 15: 6340–6350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hiroi N, Wong ML, Licinio J, Park C, Young M, Gold PW et al. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Mol Psychiatry 2001; 6: 540–546.

    Article  CAS  PubMed  Google Scholar 

  25. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci USA 1995; 92: 836–840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sanchez MM, Young LJ, Plotsky PM, Insel TR . Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 1999; 408: 365–377.

    Article  CAS  PubMed  Google Scholar 

  27. Behan DP, De Souza EB, Lowry PJ, Potter E, Sawchenko P, Vale WW . Corticotropin releasing factor (CRF) binding protein: a novel regulator of CRF and related peptides. Front Neuroendocrinol 1995; 16: 362–382.

    Article  CAS  PubMed  Google Scholar 

  28. Seasholtz AF, Valverde RA, Denver RJ . Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals. J Endocrinol 2002; 175: 89–97.

    Article  CAS  PubMed  Google Scholar 

  29. Potter E, Behan DP, Fischer WH, Linton EA, Lowry PJ, Vale WW . Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor-binding proteins. Nature 1991; 349: 423–426.

    Article  CAS  PubMed  Google Scholar 

  30. Potter E, Behan DP, Linton EA, Lowry PJ, Sawchenko PE, Vale WW . The central distribution of a corticotropin-releasing factor (CRF)-binding protein predicts multiple sites and modes of interaction with CRF. Proc Natl Acad Sci USA 1992; 89: 4192–4196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vitoratos N, Papatheodorou DC, Kalantaridou SN, Mastorakos G . ‘Reproductive’ corticotropin-releasing hormone. Ann NY Acad Sci 2006; 1092: 310–318.

    Article  CAS  PubMed  Google Scholar 

  32. Valentino RJ, Foote SL, Aston-Jones G . Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res 1983; 270: 363–367.

    Article  CAS  PubMed  Google Scholar 

  33. Tsatsanis C, Dermitzaki E, Venihaki M, Chatzaki E, Minas V, Gravanis A et al. The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function. Cell Mol Life Sci 2007; 64: 1638–1655.

    Article  CAS  PubMed  Google Scholar 

  34. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB . The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160: 1–12.

    Article  CAS  PubMed  Google Scholar 

  35. Heinrichs SC, Lapsansky J, Lovenberg TW, De Souza EB, Chalmers DT . Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. Regul Pept 1997; 71: 15–21.

    Article  CAS  PubMed  Google Scholar 

  36. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 2000; 24: 410–414.

    Article  CAS  PubMed  Google Scholar 

  37. Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 2000; 24: 403–409.

    Article  CAS  PubMed  Google Scholar 

  38. Kishimoto T, Radulovic J, Radulovic M, Lin CR, Schrick C, Hooshmand F et al. Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat Genet 2000; 24: 415–419.

    Article  CAS  PubMed  Google Scholar 

  39. Sekino A, Ohata H, Mano-Otagiri A, Arai K, Shibasaki T . Both corticotropin-releasing factor receptor type 1 and type 2 are involved in stress-induced inhibition of food intake in rats. Psychopharmacology (Berl) 2004; 176: 30–38.

    Article  CAS  Google Scholar 

  40. Valdez GR, Sabino V, Koob GF . Increased anxiety-like behavior and ethanol self-administration in dependent rats: reversal via corticotropin-releasing factor-2 receptor activation. Alcohol Clin Exp Res 2004; 28: 865–872.

    Article  CAS  PubMed  Google Scholar 

  41. Henry B, Vale W, Markou A . The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress. J Neurosci 2006; 26: 9142–9152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Takahashi LK, Ho SP, Livanov V, Graciani N, Arneric SP . Antagonism of CRF(2) receptors produces anxiolytic behavior in animal models of anxiety. Brain Res 2001; 902: 135–142.

    Article  CAS  PubMed  Google Scholar 

  43. Valdez GR, Zorrilla EP, Rivier J, Vale WW, Koob GF . Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. Brain Res 2003; 980: 206–212.

    Article  CAS  PubMed  Google Scholar 

  44. Zhao Y, Valdez GR, Fekete EM, Rivier JE, Vale WW, Rice KC et al. Subtype-selective corticotropin-releasing factor receptor agonists exert contrasting, but not opposite, effects on anxiety-related behavior in rats. J Pharmacol Exp Ther 2007; 323: 846–854.

    Article  CAS  PubMed  Google Scholar 

  45. Preil J, Muller MB, Gesing A, Reul JM, Sillaber I, van Gaalen MM et al. Regulation of the hypothalamic-pituitary-adrenocortical system in mice deficient for CRH receptors 1 and 2. Endocrinology 2001; 142: 4946–4955.

    Article  CAS  PubMed  Google Scholar 

  46. Hauger RL, Risbrough V, Brauns O, Dautzenberg FM . Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 2006; 5: 453–479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dunn AJ, Berridge CW . Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Rev 1990; 15: 71–100.

    Article  CAS  PubMed  Google Scholar 

  48. Keck ME . Corticotropin-releasing factor, vasopressin and receptor systems in depression and anxiety. Amino Acids 2006; 31: 241–250.

    Article  CAS  PubMed  Google Scholar 

  49. Keck ME, Holsboer F, Muller MB . Mouse mutants for the study of corticotropin-releasing hormone receptor function: development of novel treatment strategies for mood disorders. Ann NY Acad Sci 2004; 1018: 445–457.

    Article  CAS  PubMed  Google Scholar 

  50. Lu A, Steiner MA, Whittle N, Vogl AM, Walser SM, Ableitner M et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol Psychiatry 2008; 13: 1028–1042.

    Article  CAS  PubMed  Google Scholar 

  51. Muller 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 

  52. Kageyama K, Suda T . Regulatory mechanisms underlying corticotropin-releasing factor gene expression in the hypothalamus. Endocr J 2009; 56: 335–344.

    Article  CAS  PubMed  Google Scholar 

  53. Schulkin J, Gold PW, McEwen BS . Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load. Psychoneuroendocrinology 1998; 23: 219–243.

    Article  CAS  PubMed  Google Scholar 

  54. Keen-Rhinehart E, Michopoulos V, Toufexis DJ, Martin EI, Nair H, Ressler KJ et al. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol Psychiatry 2009; 14: 37–50.

    Article  CAS  PubMed  Google Scholar 

  55. Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB . CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987; 144: 873–877.

    Article  CAS  PubMed  Google Scholar 

  56. Hartline KM, Owens MJ, Nemeroff CB . Postmortem and cerebrospinal fluid studies of corticotropin-releasing factor in humans. Ann NY Acad Sci 1996; 780: 96–105.

    Article  CAS  PubMed  Google Scholar 

  57. Arato M, Banki CM, Bissette G, Nemeroff CB . Elevated CSF CRF in suicide victims. Biol Psychiatry 1989; 25: 355–359.

    Article  CAS  PubMed  Google Scholar 

  58. Nemeroff CB, Bissette G, Akil H, Fink M . Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin. Br J Psychiatry 1991; 158: 59–63.

    Article  CAS  PubMed  Google Scholar 

  59. De Bellis MD, Gold PW, Geracioti Jr TD, Listwak SJ, Kling MA . Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 1993; 150: 656–657.

    Article  CAS  PubMed  Google Scholar 

  60. Veith RC, Lewis N, Langohr JI, Murburg MM, Ashleigh EA, Castillo S et al. Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res 1993; 46: 1–8.

    Article  CAS  PubMed  Google Scholar 

  61. Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress Anxiety 1998; 8: 71–79.

    Article  CAS  PubMed  Google Scholar 

  62. Banki CM, Karmacsi L, Bissette G, Nemeroff CB . CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol 1992; 2: 107–113.

    Article  CAS  PubMed  Google Scholar 

  63. Austin MC, Janosky JE, Murphy HA . Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol Psychiatry 2003; 8: 324–332.

    Article  CAS  PubMed  Google Scholar 

  64. Merali Z, Kent P, Du L, Hrdina P, Palkovits M, Faludi G et al. Corticotropin-releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuromedin B alterations in stress-relevant brain regions of suicides and control subjects. Biol Psychiatry 2006; 59: 594–602.

    Article  CAS  PubMed  Google Scholar 

  65. Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF . Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436–444.

    Article  CAS  PubMed  Google Scholar 

  66. Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G . Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology 2003; 28: 1328–1335.

    Article  CAS  PubMed  Google Scholar 

  67. Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004; 24: 1478–1485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M . Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988; 45: 577–579.

    Article  CAS  PubMed  Google Scholar 

  69. Herringa RJ, Roseboom PH, Kalin NH . Decreased amygdala CRF-binding protein mRNA in post-mortem tissue from male but not female bipolar and schizophrenic subjects. Neuropsychopharmacology 2006; 31: 1822–1831.

    Article  CAS  PubMed  Google Scholar 

  70. Kozicz T, Tilburg-Ouwens D, Faludi G, Palkovits M, Roubos E . Gender-related urocortin 1 and brain-derived neurotrophic factor expression in the adult human midbrain of suicide victims with major depression. Neuroscience 2008; 152: 1015–1023.

    Article  CAS  PubMed  Google Scholar 

  71. Kunzel HE, Zobel AW, Nickel T, Ackl N, Uhr M, Sonntag A et al. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects. J Psychiatr Res 2003; 37: 525–533.

    Article  PubMed  Google Scholar 

  72. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34: 171–181.

    Article  CAS  PubMed  Google Scholar 

  73. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T . A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 2008; 165: 617–620.

    Article  PubMed  Google Scholar 

  74. Edwards VJ, Holden GW, Felitti VJ, Anda RF . Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study. Am J Psychiatry 2003; 160: 1453–1460.

    Article  PubMed  Google Scholar 

  75. Nemeroff CB . Neurobiological consequences of childhood trauma. J Clin Psychiatry 2004; 65 (Suppl 1): 18–28.

    CAS  PubMed  Google Scholar 

  76. Coplan JD, Andrews MW, Rosenblum LA, Owens MJ, Friedman S, Gorman JM et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci USA 1996; 93: 1619–1623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sanchez MM, Noble PM, Lyon CK, Plotsky PM, Davis M, Nemeroff CB et al. Alterations in diurnal cortisol rhythm and acoustic startle response in nonhuman primates with adverse rearing. Biol Psychiatry 2005; 57: 373–381.

    Article  CAS  PubMed  Google Scholar 

  78. Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Meaney MJ, Plotsky PM . Long-term behavioral and neuroendocrine adaptations to adverse early experience. Prog Brain Res 2000; 122: 81–103.

    Article  CAS  PubMed  Google Scholar 

  79. Plotsky PM, Meaney MJ . Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Mol Brain Res 1993; 18: 195–200.

    Article  CAS  PubMed  Google Scholar 

  80. Plotsky PM, Thrivikraman KV, Nemeroff CB, Caldji C, Sharma S, Meaney MJ . Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology 2005; 30: 2192–2204.

    Article  CAS  PubMed  Google Scholar 

  81. Carpenter LL, Tyrka AR, McDougle CJ, Malison RT, Owens MJ, Nemeroff CB et al. Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects. Neuropsychopharmacology 2004; 29: 777–784.

    Article  CAS  PubMed  Google Scholar 

  82. Lee R, Geracioti Jr TD, Kasckow JW, Coccaro EF . Childhood trauma and personality disorder: positive correlation with adult CSF corticotropin-releasing factor concentrations. Am J Psychiatry 2005; 162: 995–997.

    Article  PubMed  Google Scholar 

  83. Lee RJ, Gollan J, Kasckow J, Geracioti T, Coccaro EF . CSF corticotropin-releasing factor in personality disorder: relationship with self-reported parental care. Neuropsychopharmacology 2006; 31: 2289–2295.

    Article  CAS  PubMed  Google Scholar 

  84. Heim C, Mletzko T, Purselle D, Musselman DL, Nemeroff CB . The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry 2008; 63: 398–405.

    Article  CAS  PubMed  Google Scholar 

  85. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB . Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 2001; 158: 575–581.

    Article  CAS  PubMed  Google Scholar 

  86. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R et al. Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 2000; 284: 592–597.

    Article  CAS  PubMed  Google Scholar 

  87. Tyrka AR, Wier L, Price LH, Ross N, Anderson GM, Wilkinson CW et al. Childhood parental loss and adult hypothalamic-pituitary-adrenal function. Biol Psychiatry 2008; 63: 1147–1154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mathew SJ, Price RB, Charney DS . Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am J Med Genet C Semin Med Genet 2008; 148: 89–98.

    Article  CAS  Google Scholar 

  89. Risbrough VB, Stein MB . Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 2006; 50: 550–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997; 154: 624–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L et al. Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects. Biol Psychiatry 2003; 54: 1382–1388.

    Article  CAS  PubMed  Google Scholar 

  92. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK et al. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 1999; 156: 585–588.

    CAS  PubMed  Google Scholar 

  93. Banki CM, Karmacsi L, Bissette G, Nemeroff CB . Cerebrospinal fluid neuropeptides in mood disorder and dementia. J Affect Disord 1992; 25: 39–45.

    Article  CAS  PubMed  Google Scholar 

  94. Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB . Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry 1996; 39: 703–707.

    Article  CAS  PubMed  Google Scholar 

  95. Jolkkonen J, Lepola U, Bissette G, Nemeroff C, Riekkinen P . CSF corticotropin-releasing factor is not affected in panic disorder. Biol Psychiatry 1993; 33: 136–138.

    Article  CAS  PubMed  Google Scholar 

  96. Heilig M, Koob GF . A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 2007; 30: 399–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Valdez GR, Koob GF . Allostasis and dysregulation of corticotropin-releasing factor and neuropeptide Y systems: implications for the development of alcoholism. Pharmacol Biochem Behav 2004; 79: 671–689.

    Article  CAS  PubMed  Google Scholar 

  98. Adinoff B, Anton R, Linnoila M, Guidotti A, Nemeroff CB, Bissette G . Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH) and diazepam-binding inhibitor (DBI) during alcohol withdrawal and abstinence. Neuropsychopharmacology 1996; 15: 288–295.

    Article  CAS  PubMed  Google Scholar 

  99. Hawley RJ, Nemeroff CB, Bissette G, Guidotti A, Rawlings R, Linnoila M . Neurochemical correlates of sympathetic activation during severe alcohol withdrawal. Alcohol Clin Exp Res 1994; 18: 1312–1316.

    Article  CAS  PubMed  Google Scholar 

  100. Skelton KH, Nemeroff CB, Knight DL, Owens MJ . Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 2000; 20: 1240–1248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Heinrichs SC, Koob GF . Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 2004; 311: 427–440.

    Article  CAS  PubMed  Google Scholar 

  102. Kendler KS . Twin studies of psychiatric illness. Current status and future directions. Arch Gen Psychiatry 1993; 50: 905–915.

    Article  CAS  PubMed  Google Scholar 

  103. Kendler KS . Genetic epidemiology in psychiatry. Taking both genes and environment seriously. Arch Gen Psychiatry 1995; 52: 895–899.

    Article  CAS  PubMed  Google Scholar 

  104. Kendler KS, Gatz M, Gardner CO, Pedersen NL . A Swedish national twin study of lifetime major depression. Am J Psychiatry 2006; 163: 109–114.

    Article  PubMed  Google Scholar 

  105. 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 

  106. Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

    Article  CAS  PubMed  Google Scholar 

  107. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

    Article  CAS  PubMed  Google Scholar 

  108. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG et al. The sequence of the human genome. Science 2001; 291: 1304–1351.

    Article  CAS  PubMed  Google Scholar 

  109. McQueen MB, Devlin B, Faraone SV, Nimgaonkar VL, Sklar P, Smoller JW et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. Am J Hum Genet 2005; 77: 582–595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger Jr JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: bipolar disorder. Am J Hum Genet 2003; 73: 49–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Levinson DF . The genetics of depression: a review. Biol Psychiatry 2006; 60: 84–92.

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. Stratakis CA, Sarlis NJ, Berrettini WH, Badner JA, Chrousos GP, Gershon ES et al. Lack of linkage between the corticotropin-releasing hormone (CRH) gene and bipolar affective disorder. Mol Psychiatry 1997; 2: 483–485.

    Article  CAS  PubMed  Google Scholar 

  114. Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M et al. Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12. Mol Psychiatry 2003; 8: 333–342.

    Article  CAS  PubMed  Google Scholar 

  115. Marcheco-Teruel B, Flint TJ, Wikman FP, Torralbas M, Gonzalez L, Blanco L et al. A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 833–843.

    Article  CAS  PubMed  Google Scholar 

  116. Fanous AH, Neale MC, Webb BT, Straub RE, O'Neill FA, Walsh D et al. Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families. Biol Psychiatry 2008; 64: 121–127.

    Article  CAS  PubMed  Google Scholar 

  117. Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA et al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001; 98: 585–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Camp NJ, Lowry MR, Richards RL, Plenk AM, Carter C, Hensel CH et al. Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 135B: 85–93.

    Article  PubMed  Google Scholar 

  119. Hanna GL, Veenstra-Vanderweele J, Cox NJ, Van Etten M, Fischer DJ, Himle JA et al. Evidence for a susceptibility locus on chromosome 10p15 in early-onset obsessive-compulsive disorder. Biol Psychiatry 2007; 62: 856–862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  121. Brookes AJ . The essence of SNPs. Gene 1999; 234: 177–186.

    Article  CAS  PubMed  Google Scholar 

  122. Ragoussis J . Genotyping technologies for genetic research. Annu Rev Genomics Hum Genet 2009; 10: 117–133.

    Article  CAS  PubMed  Google Scholar 

  123. International HapMap Consortium. The International HapMap Project. Nature 2003; 426: 789–796.

    Article  CAS  Google Scholar 

  124. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.

    Article  CAS  Google Scholar 

  125. Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 2008; 13: 197–207.

    Article  CAS  PubMed  Google Scholar 

  126. 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 

  127. 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 

  128. Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J et al. Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry 2009; 14: 487–491.

    Article  CAS  PubMed  Google Scholar 

  129. 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 Dec 23, e-pub ahead of print.

  130. 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 

  131. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.

    Article  CAS  PubMed  Google Scholar 

  132. Shimmin LC, Natarajan S, Ibarguen H, Montasser M, Kim DK, Hanis CL et al. Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines. DNA Seq 2007; 18: 434–444.

    Article  CAS  PubMed  Google Scholar 

  133. Baerwald CG, Mok CC, Fife MS, Tikly M, Lau CS, Wordsworth BP et al. Distribution of corticotropin-releasing hormone promoter polymorphism in different ethnic groups: evidence for natural selection in human populations. Immunogenetics 1999; 49: 894–899.

    Article  CAS  PubMed  Google Scholar 

  134. Baerwald CG, Panayi GS, Lanchbury JS . A new XmnI polymorphism in the regulatory region of the corticotropin releasing hormone gene. Hum Genet 1996; 97: 697–698.

    CAS  PubMed  Google Scholar 

  135. Wagner U, Wahle M, Moritz F, Hantzschel H, Baerwald CG . Promoter polymorphisms regulating corticotrophin-releasing hormone transcription in vitro. Horm Metab Res 2006; 38: 69–75.

    Article  CAS  PubMed  Google Scholar 

  136. Wagner U, Wahle M, Malysheva O, Hantzschel H, Baerwald C . Sequence variants of the CRH 5′-flanking region: effects on DNA-protein interactions studied by EMSA in PC12 cells. Ann NY Acad Sci 2006; 1069: 20–33.

    Article  CAS  PubMed  Google Scholar 

  137. Rosmond R, Chagnon M, Bouchard C, Bjorntorp P . A polymorphism in the regulatory region of the corticotropin-releasing hormone gene in relation to cortisol secretion, obesity, and gene-gene interaction. Metabolism 2001; 50: 1059–1062.

    Article  CAS  PubMed  Google Scholar 

  138. Kyllo JH, Collins MM, Vetter KL, Cuttler L, Rosenfield RL, Donohoue PA . Linkage of congenital isolated adrenocorticotropic hormone deficiency to the corticotropin releasing hormone locus using simple sequence repeat polymorphisms. Am J Med Genet 1996; 62: 262–267.

    Article  CAS  PubMed  Google Scholar 

  139. Barr CS, Dvoskin RL, Yuan Q, Lipsky RH, Gupte M, Hu X et al. CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques. Arch Gen Psychiatry 2008; 65: 934–944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Gu J, Sadler L, Daiger S, Wells D, Wagner M . Dinucleotide repeat polymorphism at the CRH gene. Hum Mol Genet 1993; 2: 85.

    Article  CAS  PubMed  Google Scholar 

  141. Smoller JW, Rosenbaum JF, Biederman J, Kennedy J, Dai D, Racette SR et al. Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol Psychiatry 2003; 54: 1376–1381.

    Article  CAS  PubMed  Google Scholar 

  142. Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM et al. The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 2005; 57: 1485–1492.

    Article  CAS  PubMed  Google Scholar 

  143. 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 

  144. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36: 1319–1325.

    Article  CAS  PubMed  Google Scholar 

  145. Wasserman D, Sokolowski M, Rozanov V, Wasserman J . The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav 2008; 7: 14–19.

    CAS  PubMed  Google Scholar 

  146. Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi M et al. Association of polymorphisms in genes regulating the CRF system with antidepressant treatment response in the STAR*D sample. Arch Gen Psychiatry 2009 (in press).

  147. Claes S, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R et al. The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol Psychiatry 2003; 54: 867–872.

    Article  CAS  PubMed  Google Scholar 

  148. Van Den Eede F, Venken T, Del-Favero J, Norrback KF, Souery D, Nilsson LG et al. Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in recurrent major depressive disorder. Psychiatry Res 2007; 153: 17–25.

    Article  CAS  PubMed  Google Scholar 

  149. Van Den Eede F, Venken T, Van Den Bogaert A, Del-Favero J, Norrback KF, Nilsson LG et al. Single nucleotide polymorphism analysis of corticotropin-releasing factor-binding protein gene in bipolar disorder. Psychiatr Genet 2007; 17: 304–307.

    Article  PubMed  Google Scholar 

  150. Enoch MA, Shen PH, Ducci F, Yuan Q, Liu J, White KV et al. Common genetic origins for EEG, alcoholism and anxiety: the role of CRH-BP. PLoS One 2008; 3: e3620.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Catalano RD, Kyriakou T, Chen J, Easton A, Hillhouse EW . Regulation of corticotropin-releasing hormone type 2 receptors by multiple promoters and alternative splicing: identification of multiple splice variants. Mol Endocrinol 2003; 17: 395–410.

    Article  CAS  PubMed  Google Scholar 

  152. Ardati A, Goetschy V, Gottowick J, Henriot S, Valdenaire O, Deuschle U et al. Human CRF2 alpha and beta splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay. Neuropharmacology 1999; 38: 441–448.

    Article  CAS  PubMed  Google Scholar 

  153. Kostich WA, Chen A, Sperle K, Largent BL . Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor. Mol Endocrinol 1998; 12: 1077–1085.

    CAS  PubMed  Google Scholar 

  154. Valdenaire O, Giller T, Breu V, Gottowik J, Kilpatrick G . A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochim Biophys Acta 1997; 1352: 129–132.

    Article  CAS  PubMed  Google Scholar 

  155. Nanda SA, Roseboom PH, Nash GA, Speers JM, Kalin NH . Characterization of the human corticotropin-releasing factor2(a) receptor promoter: regulation by glucocorticoids and the cyclic adenosine 5′-monophosphate pathway. Endocrinology 2004; 145: 5605–5615.

    Article  CAS  PubMed  Google Scholar 

  156. Tochigi M, Kato C, Otowa T, Hibino H, Marui T, Ohtani T et al. Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits. Psychiatry Clin Neurosci 2006; 60: 524–526.

    Article  CAS  PubMed  Google Scholar 

  157. De Luca V, Tharmalingam S, Kennedy JL . Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder. Eur Psychiatry 2007; 22: 282–287.

    Article  PubMed  Google Scholar 

  158. Papiol S, Arias B, Gasto C, Gutierrez B, Catalan R, Fananas L . Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment. J Affect Disord 2007; 104: 83–90.

    Article  CAS  PubMed  Google Scholar 

  159. Tharmalingam S, King N, De Luca V, Rothe C, Koszycki D, Bradwejn J et al. Lack of association between the corticotrophin-releasing hormone receptor 2 gene and panic disorder. Psychiatr Genet 2006; 16: 93–97.

    Article  PubMed  Google Scholar 

  160. Villafuerte SM, Del-Favero J, Adolfsson R, Souery D, Massat I, Mendlewicz J et al. Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression. Am J Med Genet 2002; 114: 222–226.

    Article  PubMed  Google Scholar 

  161. Grammatopoulos DK, Chrousos GP . Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab 2002; 13: 436–444.

    Article  CAS  PubMed  Google Scholar 

  162. Pisarchik A, Slominski A . Molecular and functional characterization of novel CRFR1 isoforms from the skin. Eur J Biochem 2004; 271: 2821–2830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ross PC, Kostas CM, Ramabhadran TV . A variant of the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology. Biochem Biophys Res Commun 1994; 205: 1836–1842.

    Article  CAS  PubMed  Google Scholar 

  164. Pisarchik A, Slominski AT . Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. FASEB J 2001; 15: 2754–2756.

    Article  CAS  PubMed  Google Scholar 

  165. Jin D, He P, You X, Zhu X, Dai L, He Q et al. Expression of corticotropin-releasing hormone receptor type 1 and type 2 in human pregnant myometrium. Reprod Sci 2007; 14: 568–577.

    Article  CAS  PubMed  Google Scholar 

  166. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J et al. A common inversion under selection in Europeans. Nat Genet 2005; 37: 129–137.

    Article  CAS  PubMed  Google Scholar 

  167. Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 2006; 38: 999–1001.

    Article  CAS  PubMed  Google Scholar 

  168. Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006; 38: 1038–1042.

    Article  CAS  PubMed  Google Scholar 

  169. Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 2006; 38: 1032–1037.

    Article  CAS  PubMed  Google Scholar 

  170. Tan TY, Aftimos S, Worgan L, Susman R, Wilson M, Ghedia S et al. Phenotypic expansion and further characterization of the 17q21.31 microdeletion syndrome. J Med Genet 2009; 46: 480–489.

    Article  CAS  PubMed  Google Scholar 

  171. Tan TY, Aftimos S, Worgan L, Susman R, Wilson M, Ghedia S et al. Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome. J Med Genet 2009; 46: 480–489.

    Article  CAS  PubMed  Google Scholar 

  172. Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M . A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet 2007; 50: 256–263.

    Article  PubMed  Google Scholar 

  173. 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 

  174. Licinio J, O'Kirwan F, Irizarry K, Merriman B, Thakur S, Jepson R et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol Psychiatry 2004; 9: 1075–1082.

    Article  CAS  PubMed  Google Scholar 

  175. Liu Z, Zhu F, Wang G, Xiao Z, Tang J, Liu W et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders. Neurosci Lett 2007; 414: 155–158.

    Article  CAS  PubMed  Google Scholar 

  176. Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci Lett 2006; 404: 358–362.

    Article  CAS  PubMed  Google Scholar 

  177. Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 2008; 65: 190–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wasserman D, Sokolowski M, Rozanov V, Wasserman J . The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav 2008; 7: 14–19.

    CAS  PubMed  Google Scholar 

  179. Polanczyk G, Caspi A, Williams B, Price TS, Danese A, Sugden K et al. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch Gen Psychiatry 2009; 66: 978–985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Tyrka AR, Price LH, Gelernter J, Schepker C, Anderson GM, Carpenter LL . Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psychiatry 2009; 66: 681–685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Heim CM, Bradley B, Mletzko T, Deveau TC, Musselman DL, Nemeroff CB et al. Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front Behav Neurosci 2009 (in press).

  182. Ressler KJ, Bradley B, Mercer KB, Deveau TC, Smith AK, Gillespie CF et al. Polymorphisms in CRHR1 and the serotonin transporter loci: gene × gene × environment interactions on depressive symptoms. Am J Med Genet B Psychiatric Genet 2009 (in press).

  183. Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, Laucht M . Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol Psychiatry 2008; 63: 146–151.

    Article  CAS  PubMed  Google Scholar 

  184. Schmid B, Blomeyer D, Treutlein J, Zimmermann US, Buchmann AF, Schmidt MH et al. Interacting effects of CRHR1 gene and stressful life events on drinking initiation and progression among 19-year-olds. Int J Neuropsychopharmacol 2009; 17: 1–12.

    Google Scholar 

  185. Barr CS, Dvoskin RL, Gupte M, Sommer W, Sun H, Schwandt ML et al. Functional CRH variation increases stress-induced alcohol consumption in primates. Proc Natl Acad Sci USA 2009; 106: 14593–14598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Derijk RH, de Kloet ER . Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience. Eur J Pharmacol 2008; 583: 303–311.

    Article  CAS  PubMed  Google Scholar 

  187. Binder EB . The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 2009; 34: 99–109.

    Article  CAS  PubMed  Google Scholar 

  188. Mueller BR, Bale TL . Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 2008; 28: 9055–9065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Szyf M . The early life environment and the epigenome. Biochim Biophys Acta 2009; 1790: 878–885.

    Article  CAS  PubMed  Google Scholar 

  190. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 2008; 82: 696–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Support was received from NIH grants MH-42088, MH-69056, MH-58922 and RR-25008. Dr Binder is supported by a Doris Duke Clinical Scientist Development Award.

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Authors and Affiliations

  1. Max-Planck Institute of Psychiatry, Munich, Germany

    E B Binder

  2. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Munich, Germany

    E B Binder

  3. Department of Human Genetics, Emory University School of Medicine, Munich, Germany

    E B Binder

  4. Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    C B Nemeroff

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Currently, Dr Nemeroff serves on the Scientific Advisory Board for the American Foundation for Suicide Prevention; AstraZeneca; NARSAD, PharmaNeuroboost and CeNeRx. He serves on the Board of Directors of American Foundation for Suicide Prevention; George West Mental Health Foundation; NovaDel Pharma, Mt Cook Pharma, Inc. He owns equity or is stock holder in Corcept; Revaax; NovaDel Pharma; CeNeRx, PharmaNeuroboost, Mt Cook Pharma. He is inventor on the following patents: method and devices for transdermal delivery of lithium (US 6,375,990 B1) and method to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April, 2001). Currently, Dr Binder receives grant support from NIMH and the Doris Duke charitable foundation.

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Binder, E., Nemeroff, C. The CRF system, stress, depression and anxiety—insights from human genetic studies. Mol Psychiatry 15, 574–588 (2010). https://doi.org/10.1038/mp.2009.141

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