Metabolic Brain Disease

, Volume 33, Issue 2, pp 601–613 | Cite as

Hypothalamic-pituitary-adrenal axis variants and childhood trauma influence anxiety sensitivity in South African adolescents

  • Jacqueline S. Womersley
  • Lindi I. Martin
  • Lize van der Merwe
  • Soraya Seedat
  • Sian M. J. Hemmings
Original Article


Anxiety sensitivity (AS) is characterised by the fear of anxiety-related symptoms and is a risk factor for the development of anxiety-related disorders. We examined whether genetic variation in three stress response genes, CRHR1, NR3C1, and FKBP5, interact with childhood trauma (CT) to predict AS in South African adolescents. Xhosa (n = 634) and Coloured (n = 317) students completed self-report measures of AS and CT, and a total of eighteen polymorphisms within CRHR1, NR3C1, and FKBP5 were genotyped. Differences in AS based on genetic variation and CT were analysed within population and gender groups using multiple linear regression. Associations were found between AS and FKBP5 rs9296158 (p = 0.025) and rs737054 (p = 0.045) in Coloured males. Analysis of gene x CT interactions indicated that NR3C1 rs190488 CC-genotype, NR3C1 rs10482605 G-allele addition, and FKBP5 rs3800373 C-allele addition protect against AS with increasing CT in Xhosa females (p = 0.009), Xhosa males (p = 0.036) and Coloured males (p = 0.049), respectively. We identified two different protective single nucleotide polymorphism (SNP) combinations in a four-SNP CRHR1 haplotype in Coloured males. An analysis of the interaction between CT and a six-SNP FKBP5 haplotype in Coloured males revealed both protective and risk allelic combinations. Our results provide evidence for the influence of both genetic variation in CRHR1, NR3C1 and FKBP5, as well as CT x SNP interactions, on AS in South African adolescents. This study reinforces the importance of examining the influence of gene-environment (G X E) interactions within gender and population groups.


Anxiety CRHR1 FKBP5 Genetics Hypothalamic-pituitary-adrenal axis NR3C1 



This study was supported by a South African Medical Research Council (MRC) Self-initiated Research grant (PI: S. Hemmings). This work is based upon research supported by the South African Research Chairs Initiative in PTSD of the Department of Science and Technology and the National Research Foundation.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendment or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11011_2017_138_MOESM1_ESM.docx (24 kb)
Supplementary Table 1 (DOCX 24 kb)


  1. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro MG (2001) Alcohol user disorders identification test. Guidelines for use in primary care, 2nd edn. Geneva, Switzerland: World Health OrganizationGoogle Scholar
  2. Belsky J, Jonassaint C, Pluess M et al (2009) Vulnerability genes or plasticity genes? Mol Psychiatry 14:746–754. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bernstein DP, Fink L (1998) Manual for the childhood trauma questionnaire: a retrospective self-report. The Psychological Corporation. Harcourt Brace, New YorkGoogle Scholar
  4. Binder EB, Bradley RG, Liu W et al (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299:1291.
  5. Binder EB, Nemeroff CB (2010) The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry 15:574–588. CrossRefPubMedGoogle Scholar
  6. Bortoluzzi A, Blaya C, da Rosa ED et al (2015) What can HPA axis-linked genes tell us about anxiety disorders in adolescents? Trends Psychiatry Psychother 37:232–237. CrossRefPubMedGoogle Scholar
  7. Bradley RG, Binder EB, Epstein MP et al (2008) Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 65:190. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Buchmann AF, Holz N, Boecker R et al (2014) Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood. Eur Neuropsychopharmacol 24:837–845. CrossRefPubMedGoogle Scholar
  9. Carpenter LL, Tyrka AR, Ross NS et al (2009) Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biol Psychiatry 66:69–75CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chimusa ER, Meintjies A, Tchanga M et al (2015) A genomic portrait of haplotype diversity and signatures of selection in indigenous southern African populations. PLoS Genet 11:e1005052. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Connor KM, Davidson JRT (2003) Development of a new resilience scale: the Connor-Davidson resilience scale (CD-RISC). Depress Anxiety 18:76–82. CrossRefPubMedGoogle Scholar
  12. Davies TH, Ning Y-M, Sánchez ER (2002) A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem 277:4597–4600. CrossRefPubMedGoogle Scholar
  13. Davies TH, Ning Y-M, Sánchez ER (2005) Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506 . Biochemistry (Mosc) 44:2030–2038. CrossRefGoogle Scholar
  14. Daya M, van der Merwe L, Galal U et al (2013) A panel of ancestry informative markers for the complex five-way admixed south African coloured population. PLoS One 8:e82224. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Dmitrzak-Weglarz M, Szczepankiewicz A, Slopien A et al (2016) Association of the glucocorticoid receptor gene polymorphisms and their interaction with stressful life events in Polish adolescent girls with anorexia nervosa. Psychiatr Danub 28:51–57PubMedGoogle Scholar
  16. Gene Portal of the National Center for Biotechnology (2017) Accessed 28 Feb 2017
  17. Glaser D (2000) Child abuse and neglect and the brain-a review. J Child Psychol Psychiatry 41:97–116. CrossRefPubMedGoogle Scholar
  18. Gunnar MR, Donzella B (2002) Social regulation of the cortisol levels in early human development. Psychoneuroendocrinology 27:199–220CrossRefPubMedGoogle Scholar
  19. Hemmings SMJ, Martin LI, van der Merwe L et al (2016) Serotonin transporter variants play a role in anxiety sensitivity in south African adolescents. World J Biol Psychiatry 17:66–75. CrossRefPubMedGoogle Scholar
  20. Huizenga NATM, Koper JW, de Lange P et al (1998) A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in Vivo 1. J Clin Endocrinol Metab 83:144–151. PubMedGoogle Scholar
  21. Ising M, Depping A-M, Siebertz A et al (2008) Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. Eur J Neurosci 28:389–398. CrossRefPubMedGoogle Scholar
  22. Jacobson L (2014) Hypothalamic-pituitary-adrenocortical Axis: neuropsychiatric aspects: HPA Axis. In: Terjung R (ed) Comprehensive physiology. Hoboken, Wiley, pp 715–738CrossRefGoogle Scholar
  23. Klengel T, Binder EB (2015) FKBP5 allele-specific epigenetic modification in gene by environment interaction. Neuropsychopharmacology 40:244–246. CrossRefPubMedGoogle Scholar
  24. Kohrt BA, Worthman CM, Ressler KJ et al (2015) Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia. Int Rev Psychiatry Abingdon Engl 27:180–196. CrossRefGoogle Scholar
  25. Kumsta R, Entringer S, Koper JW et al (2007) Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal Axis responses to psychosocial stress. Biol Psychiatry 62:863–869. CrossRefPubMedGoogle Scholar
  26. Kumsta R, Moser D, Streit F et al (2009) Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance. Am J Med Genet B Neuropsychiatr Genet 150B:476–482. CrossRefPubMedGoogle Scholar
  27. Mahon PB, Zandi PP, Potash JB et al (2013) Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults. Psychopharmacology 227:231–241. CrossRefPubMedGoogle Scholar
  28. Maller RG, Reiss S (1992) Anxiety sensitivity in 1984 and panic attacks in 1987. J Anxiety Disord 6:241–247. CrossRefGoogle Scholar
  29. Martin L, Viljoen M, Kidd M, Seedat S (2014) Are childhood trauma exposures predictive of anxiety sensitivity in school attending youth? J Affect Disord 168:5–12. CrossRefPubMedGoogle Scholar
  30. McLaughlin KA, Hatzenbuehler ML (2009) Stressful life events, anxiety sensitivity, and internalizing symptoms in adolescents. J Abnorm Psychol 118:659–669. CrossRefPubMedPubMedCentralGoogle Scholar
  31. McNally RJ (1989) Is anxiety sensitivity distinguishable from trait anxiety? Reply to Lilienfeld, Jacob, and Turner (1989). J Abnorm Psychol 98:193–194. CrossRefPubMedGoogle Scholar
  32. Mihaljevic M, Zeljic K, Soldatovic I et al (2016) The emerging role of the FKBP5 gene polymorphisms in vulnerability–stress model of schizophrenia: further evidence from a Serbian population. Eur Arch Psychiatry Clin Neurosci.
  33. Millis MP (2011) Medium-throughput SNP genotyping using mass spectrometry: multiplex SNP genotyping using the iPLEX® gold assay. In: DiStefano JK (ed) Disease gene identification. Humana Press, Totowa, pp 61–76CrossRefGoogle Scholar
  34. National Cancer Institute NCIthesaurus (2017) Accessed 10 Mar 2017
  35. Nugent NR, Tyrka AR, Carpenter LL, Price LH (2011) Gene–environment interactions: early life stress and risk for depressive and anxiety disorders. Psychopharmacology 214:175–196. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Pagliaccio D, Luby JL, Bogdan R et al (2015) HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children. NeuroImage 109:1–11. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Panek M, Pietras T, Szemraj J, Kuna P (2014) Association analysis of the glucocorticoid receptor gene (NR3C1) haplotypes (ER22/23EK, N363S, BclI) with mood and anxiety disorders in patients with asthma. Exp Ther Med.
  38. Patterson JM, McCubbin HI (1987) Adolescent coping style and behaviors: conceptualization and measurement. J Adolesc 10:163–186CrossRefPubMedGoogle Scholar
  39. Patterson N, Petersen DC, van der Ross RE et al (2010) Genetic structure of a unique admixed population: implications for medical research. Hum Mol Genet 19:411–419. CrossRefPubMedGoogle Scholar
  40. Perkel J (2008) SNP genotyping: six technologies that keyed a revolution. Nat Methods 5:447–453. CrossRefGoogle Scholar
  41. Pirkl F, Buchner J (2001) Functional analysis of the hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and cyp40. J Mol Biol 308:795–806. CrossRefPubMedGoogle Scholar
  42. R Development Core Team (2017) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  43. Ridder S, Treutlein J, Nees F et al (2012) Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic–pituitary–adrenal axis: first evidence from two independent subsamples. Psychol Med 42:2325–2335. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Scheuer S, Ising M, Uhr M et al (2016) FKBP5 polymorphisms moderate the influence of adverse life events on the risk of anxiety and depressive disorders in preschool children. J Psychiatr Res 72:30–36. CrossRefPubMedGoogle Scholar
  45. Schiene-Fischer C, Yu C (2001) Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Lett 495:1–6CrossRefPubMedGoogle Scholar
  46. Schmidt NB, Keough ME, Timpano KR, Richey JA (2008) Anxiety sensitivity profile: predictive and incremental validity. J Anxiety Disord 22:1180–1189. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Seedat M, Van Niekerk A, Jewkes R et al (2009) Violence and injuries in South Africa: prioritising an agenda for prevention. Lancet 374:1011–1022. CrossRefPubMedGoogle Scholar
  48. Silverman WK, Fleisig W, Rabian B, Peterson RA (1991) Childhood anxiety sensitivity index. J Clin Child Psychol 20:162–168. CrossRefGoogle Scholar
  49. Sinwell JP, Schaid DJ (2016) Haplo.stats: Statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. Version 1.7.7Google Scholar
  50. Spielberger CD (1973) Manual for the state-trait anxiety inventory for children. Consulting Psychologists Press, Inc., Palo AltoGoogle Scholar
  51. Stein MB, Jang KL, Livesley WJ (1999) Heritability of anxiety sensitivity: a twin study. Am J Psychiatry 156:246–251. PubMedGoogle Scholar
  52. Stewart SH, Taylor S, Baker JM (1997) Gender differences in dimensions of anxiety sensitivity. J Anxiety Disord 11:179–200CrossRefPubMedGoogle Scholar
  53. Stoltenborgh M, Bakermans-Kranenburg MJ, van Ijzendoorn MH (2013) The neglect of child neglect: a meta-analytic review of the prevalence of neglect. Soc Psychiatry Psychiatr Epidemiol 48:345–355. CrossRefPubMedGoogle Scholar
  54. Tarullo AR, Gunnar MR (2006) Child maltreatment and the developing HPA axis. Horm Behav 50:632–639. CrossRefPubMedGoogle Scholar
  55. Taylor S, Koch WJ, McNally RJ (1992) How does anxiety sensitivity vary across the anxiety disorders? J Anxiety Disord 6:249–259. CrossRefGoogle Scholar
  56. Taylor S, Jang KL, Stewart SH, Stein MB (2008) Etiology of the dimensions of anxiety sensitivity: a behavioral–genetic analysis. J Anxiety Disord 22:899–914. CrossRefPubMedGoogle Scholar
  57. Tyrka AR, Price LH, Gelernter J et al (2009) Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psychiatry 66:681–685. CrossRefPubMedPubMedCentralGoogle Scholar
  58. van Rossum EFC, Koper JW, van den Beld AW et al (2003) Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol 59:585–592CrossRefGoogle Scholar
  59. van West D, Del-Favero J, Deboutte D et al (2010) Associations between common arginine vasopressin 1b receptor and glucocorticoid receptor gene variants and HPA axis responses to psychosocial stress in a child psychiatric population. Psychiatry Res 179:64–68. CrossRefPubMedGoogle Scholar
  60. van Zuiden M, Geuze E, Willemen HLDM et al (2012) Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study. Biol Psychiatry 71:309–316. CrossRefPubMedGoogle Scholar
  61. Weber H, Richter J, Straube B et al (2016) Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Mol Psychiatry 21:813–822. CrossRefPubMedGoogle Scholar
  62. Weissman MM, Orvaschel H, Padian N (1980) Children’s symptom and social functioning self-report scales. Comparison of mothers’ and children’s reports. J Nerv Ment Dis 168:736–740CrossRefPubMedGoogle Scholar
  63. Williams SL, Williams DR, Stein DJ et al (2007) Multiple traumatic events and psychological distress: the South Africa stress and health study. J Trauma Stress 20:845–855. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Willour VL, Chen H, Toolan J et al (2009) Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry 14:261–268. CrossRefPubMedGoogle Scholar
  65. World Health Organisation (2016) Child maltreatment fact sheet. Accessed 3 Apr 2017
  66. Xie P, Kranzler HR, Poling J et al (2010) Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology.
  67. Zannas AS, Binder EB (2014) Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism: FKBP5 and gene-environment interactions. Genes Brain Behav 13:25–37. CrossRefPubMedGoogle Scholar
  68. Zavos HMS, Gregory AM, Eley TC (2012) Longitudinal genetic analysis of anxiety sensitivity. Dev Psychol 48:204–212. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Jacqueline S. Womersley
    • 1
  • Lindi I. Martin
    • 1
  • Lize van der Merwe
    • 2
  • Soraya Seedat
    • 1
  • Sian M. J. Hemmings
    • 1
  1. 1.Department of Psychiatry, Faculty of Medicine and Health SciencesStellenbosch UniversityTygerbergSouth Africa
  2. 2.Department of Human Genetics, Faculty of AgricultureStellenbosch UniversityStellenboschSouth Africa

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