Skip to main content

Advertisement

SpringerLink
Log in

Association between a common CYP17A1 haplotype and anxiety in female anorexia nervosa

  • Original Article
  • Published:
Archives of Women's Mental Health Aims and scope Submit manuscript

Abstract

Dehydroepiandrosterone (DHEA), the main brain neurosteroid, has been implicated in various psychiatric disorders especially those including gender differences. We studied genetic variability in the DHEA-producing enzyme CYP17A1 in relation to anorexia nervosa (AN) susceptibility and AN-related co-morbidities. We performed analysis of 100 Israeli AN family trios accounting for CYP17A1 haplotypes characteristic of populations of European origin and studied genotype–phenotype relationships using correlation analyses and transmission disequilibrium test. Although our analysis revealed no evidence of association between CYP17A1 and AN per se, it revealed an association between specific CYP17A1 haplotypes and AN co-morbidity, specifically anxiety. We found that a common CYP17A1 haplotype (H1) was associated with higher anxiety in AN patients (Clinical Global Impression; CGI-anxiety ≥4). Moreover, H1 homozygotes were at higher risk for expressing high CGI-anxiety levels (OR = 3.7), and H1 was preferentially transmitted to AN patients with high CGI-anxiety levels (P = 0. 037). We suggest that CYP17A1 H1 haplotype may contribute to genetic predisposition to higher CGI-anxiety levels in AN patients and that this predisposition may be mediated by reduced CYP17A1 enzymatic activity and corresponding lower DHEA production.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Baulieu EE, Robel P (1998) Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci U S A 95(8):4089–4091

    Article  PubMed  CAS  Google Scholar 

  • Berkman ND, Lohr KN, Bulik CM (2007) Outcomes of eating disorders: a systematic review of the literature. Int J Eat Disord 40(4):293–309

    Article  PubMed  Google Scholar 

  • Birmingham CL, Su J, Hlynsky JA, Goldner EM, Gao M (2005) The mortality rate from anorexia nervosa. Int J Eat Disord 38(2):143–146

    Article  PubMed  Google Scholar 

  • Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL (2006) Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 63(3):305–312

    Article  PubMed  Google Scholar 

  • Chakraborty A, Murthy NS, Chintamani C, Bhatnagar D, Mohil RS, Sharma PC, Saxena S (2007) CYP17 gene polymorphism and its association with high-risk north Indian breast cancer patients. J Hum Genet 52(2):159–165

    Article  PubMed  Google Scholar 

  • Eastwood H, Brown KM, Markovic D, Pieri LF (2002) Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa. Mol Psychiatry 7(1):86–89

    Article  PubMed  CAS  Google Scholar 

  • Feigelson HS, Shames LS, Pike MC, Coetzee GA, Stanczyk FZ, Henderson BE (1998) Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res 58(4):585–587

    PubMed  CAS  Google Scholar 

  • Frisch A, Laufer N, Danziger Y, Michaelovsky E, Leor S, Carel C, Stein D, Fenig S, Mimouni M, Apter A, Weizman A (2001) Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. Mol Psychiatry 6(2):243–245

    Article  PubMed  CAS  Google Scholar 

  • Gervasini G, Gordillo I, Garcia-Herraiz A, Flores I, Jimenez M, Monge M, Carrillo JA (2012) Polymorphisms in serotonergic genes and psychopathological traits in eating disorders. J Clin Psychopharmacol 32(3):426–428

    Article  PubMed  Google Scholar 

  • Godart NT, Flament MF, Perdereau F, Jeammet P (2002) Comorbidity between eating disorders and anxiety disorders: a review. Int J Eat Disord 32(3):253–270

    Article  PubMed  CAS  Google Scholar 

  • Godart NT, Perdereau F, Rein Z, Berthoz S, Wallier J, Jeammet P, Flament MF (2007) Comorbidity studies of eating disorders and mood disorders. Critical review of the literature. J Affect Disord 97(1–3):37–49

    Article  PubMed  CAS  Google Scholar 

  • Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002) Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metabol 87(11):4935–4941

    Article  CAS  Google Scholar 

  • Guy W (1976) Clinical global impression (CGI). US Department of Health, Education and Welfare, Rockville, MD

  • Haiman CA, Hankinson SE, Spiegelman D, Colditz GA, Willett WC, Speizer FE, Kelsey KT, Hunter DJ (1999) The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res 59(5):1015–1020

    PubMed  CAS  Google Scholar 

  • Henningson M, Johansson U, Borg A, Olsson H, Jernstrom H (2007) CYP17 genotype is associated with short menstrual cycles, early oral contraceptive use and BRCA mutation status in young healthy women. Mol Hum Reprod 13(4):231–236

    Article  PubMed  CAS  Google Scholar 

  • Holtkamp K, Muller B, Heussen N, Remschmidt H, Herpertz-Dahlmann B (2005) Depression, anxiety, and obsessionality in long-term recovered patients with adolescent-onset anorexia nervosa. Eur Child Adolesc Psychiatry 14(2):106–110

    Article  PubMed  CAS  Google Scholar 

  • Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9(4):301–306

    Article  PubMed  CAS  Google Scholar 

  • Juhasz-Vedres G, Rozsa E, Rakos G, Dobszay MB, Kis Z, Wolfling J, Toldi J, Parducz A, Farkas T (2006) Dehydroepiandrosterone sulfate is neuroprotective when administered either before or after injury in a focal cortical cold lesion model. Endocrinology 147(2):683–686

    Article  PubMed  CAS  Google Scholar 

  • Klump KL, Gobrogge KL (2005) A review and primer of molecular genetic studies of anorexia nervosa. Int J Eat Disord 37(Suppl):S43–S48, Discussion S87-49

    Article  PubMed  Google Scholar 

  • Koronyo-Hamaoui M, Danziger Y, Frisch A, Stein D, Leor S, Laufer N, Carel C, Fennig S, Minoumi M, Apter A, Goldman B, Barkai G, Weizman A, Gak E (2002) Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study. Mol Psychiatry 7(1):82–85

    Article  PubMed  CAS  Google Scholar 

  • Koronyo-Hamaoui M, Frisch A, Stein D, Denziger Y, Leor S, Michaelovsky E, Laufer N, Carel C, Fennig S, Mimouni M, Ram A, Zubery E, Jeczmien P, Apter A, Weizman A, Gak E (2007) Dual contribution of NR2B subunit of NMDA receptor and SK3 Ca(2+)-activated K+ channel to genetic predisposition to anorexia nervosa. J Psychiatr Res 41(1–2):160–167

    Article  PubMed  Google Scholar 

  • Lapchak PA, Araujo DM (2001) Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol 46:379–397

    Article  PubMed  CAS  Google Scholar 

  • Le Melledo JM, Baker G (2004) Role of progesterone and other neuroactive steroids in anxiety disorders. Expert Rev Neurother 4(5):851–860

    Article  PubMed  Google Scholar 

  • Michaelovsky E, Frisch A, Leor S, Stein D, Danziger Y, Carel C, Fennig S, Mimouni M, Klauck SM, Benner A, Poustka A, Apter A, Weizman A (2005) Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios. Am J Med Genet B Neuropsychiatr Genet 139B(1):45–50

    Article  PubMed  CAS  Google Scholar 

  • Milos G, Spindler A, Ruggiero G, Klaghofer R, Schnyder U (2002) Comorbidity of obsessive-compulsive disorders and duration of eating disorders. Int J Eat Disord 31(3):284–289

    Article  PubMed  Google Scholar 

  • Monteleone P, Luisi M, Colurcio B, Casarosa E, Monteleone P, Ioime R, Genazzani AR, Maj M (2001) Plasma levels of neuroactive steroids are increased in untreated women with anorexia nervosa or bulimia nervosa. Psychosom Med 63(1):62–68

    PubMed  CAS  Google Scholar 

  • Monteleone P, Luisi M, Martiadis V, Serritella C, Longobardi N, Casarosa E, Genazzani AR, Maj M (2006) Impaired reduction of enhanced levels of dehydroepiandrosterone by oral dexamethasone in anorexia nervosa. Psychoneuroendocrinology 31(4):537–542

    Article  PubMed  CAS  Google Scholar 

  • Mukai H, Tsurugizawa T, Ogiue-Ikeda M, Murakami G, Hojo Y, Ishii H, Kimoto T, Kawato S (2006) Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. Neuroendocrinology 84(4):255–263

    Article  PubMed  CAS  Google Scholar 

  • Perdereau F, Faucher S, Wallier J, Vibert S, Godart N (2008) Family history of anxiety and mood disorders in anorexia nervosa: review of the literature. Eat Weight Disord 13(1):1–13

    PubMed  CAS  Google Scholar 

  • Ritsner M, Maayan R, Gibel A, Weizman A (2007) Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol 17(5):358–365

    Article  PubMed  CAS  Google Scholar 

  • Rosenkranz K, Hinney A, Ziegler A, Hermann H, Fichter M, Mayer H, Siegfried W, Young JK, Remschmidt H, Hebebrand J (1998) Systematic mutation screening of the estrogen receptor beta gene in probands of different weight extremes: identification of several genetic variants. J Clin Endocrinol Metabol 83(12):4524–4527

    Article  CAS  Google Scholar 

  • Rupprecht R, di Michele F, Hermann B, Strohle A, Lancel M, Romeo E, Holsboer F (2001) Neuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology. Brain Res Brain Res Rev 37(1–3):59–67

    Article  PubMed  CAS  Google Scholar 

  • Sarkar DK, Friedman SJ, Yen SS, Frautschy SA (1989) Chronic inhibition of hypothalamic-pituitary-ovarian axis and body weight gain by brain-directed delivery of estradiol-17 beta in female rats. Neuroendocrinology 50(2):204–210

    Article  PubMed  CAS  Google Scholar 

  • Small CM, Marcus M, Sherman SL, Sullivan AK, Manatunga AK, Feigelson HS (2005) CYP17 genotype predicts serum hormone levels among pre-menopausal women. Hum Reprod 20(8):2162–2167

    Article  PubMed  CAS  Google Scholar 

  • Sobti RC, Gupta L, Thakur H, Seth A, Singh SK, Kaur P (2009) CYP17 gene polymorphism and its association in north Indian prostate cancer patients. Anticancer Res 29(5):1659–1663

    PubMed  CAS  Google Scholar 

  • Stein D, Maayan R, Ram A, Loewenthal R, Achiron A, Modan-Moses D, Feigin M, Weizman A, Valevski A (2005) Circulatory neurosteroid levels in underweight female adolescent anorexia nervosa inpatients and following weight restoration. Eur Neuropsychopharmacol 15(6):647–653

    Article  PubMed  CAS  Google Scholar 

  • Strous RD, Maayan R, Weizman A (2006) The relevance of neurosteroids to clinical psychiatry: from the laboratory to the bedside. Eur Neuropsychopharmacol 16(3):155–169

    Article  PubMed  CAS  Google Scholar 

  • Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ, Berrettini W, Hakonarson H (2011) A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 16(9):949–959

    Article  PubMed  CAS  Google Scholar 

  • Yazici H, Tigli H, Kadehci Z, Kucucuk S, Saip P, Issever H, Ozcelik H, Dalay N (2006) Are CYP17 genotypes a biomarker for ovarian cancer in patients with cancer history in their family? Oncol Res 16(1):43–47

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Israeli Ministry of Health Chief Scientist grant no. 3000003229 and made part of the M.Sc. thesis of Efrat Czerniak at the Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University. We gratefully acknowledge the Assi Schneidman foundation for partial support of this study.

Conflict of interest

All authors report no actual or potential conflicts of interests including any financial, personal, or other relationships with people or organization that could influence this research.

Author information

Authors and Affiliations

  1. Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel

    Efrat Czerniak, Michael Korostishevsky, Amos Frisch, Gideon Rechavi, Elena Michaelovsky, Daniel Stein, Alan Apter & Abraham Weizman

  2. Felsenstein Medical Research Center, Petach Tikva, Israel

    Amos Frisch, Elena Michaelovsky, Alan Apter & Abraham Weizman

  3. Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Daniel Stein

  4. Feinberg Child Study Center, Schneider Children’s Medical Center, Petach Tikva, Israel

    Yardena Danziger, Silvana Fennig & Alan Apter

  5. Geha Psychiatric Hospital, Petach Tikva, Israel

    Abraham Weizman

  6. Joseph Sagol Neuroscience Center (JSNC), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Efrat Czerniak

  7. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel

    Eva Gak

  8. Sheba Cancer Research Center (SCRC), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Yoram Cohen, Ninette Amariglio & Gideon Rechavi

  9. Eating Disorders Unit, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel

    Daniel Stein

Authors
  1. Efrat Czerniak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Korostishevsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amos Frisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoram Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ninette Amariglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gideon Rechavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elena Michaelovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yardena Danziger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Silvana Fennig
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alan Apter
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Abraham Weizman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eva Gak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eva Gak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Czerniak, E., Korostishevsky, M., Frisch, A. et al. Association between a common CYP17A1 haplotype and anxiety in female anorexia nervosa. Arch Womens Ment Health 16, 423–428 (2013). https://doi.org/10.1007/s00737-013-0363-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00737-013-0363-x

Keywords

Search

Navigation