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Abstract

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality1 as well as the treatment of depression2. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

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References

  1. 1.

    The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).

  2. 2.

    & Treatment of mood disorders. Nat. Neurosci. 5, 1068–1070 (2002).

  3. 3.

    & Antidepressants and hypothalamic–pituitary–adrenocortical regulation. Endocr. Rev. 17, 187–205 (1996).

  4. 4.

    The role of corticotropin–releasing factor in the pathogenesis of major depression. Pharmacopsychiatry 21, 76–82 (1988).

  5. 5.

    et al. Elevated concentrations of CSF corticotropin–releasing factor–like immunoreactivity in depressed patients. Science 226, 1342–1344 (1984).

  6. 6.

    , , , & Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch. Gen. Psychiatry 45, 577–579 (1988).

  7. 7.

    , , & Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiatry 53, 137–143 (1996).

  8. 8.

    et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin–releasing hormone receptor. Nat. Genet. 19, 162–166 (1998).

  9. 9.

    et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 6, 1100–1107 (2003).

  10. 10.

    & Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391–404 (2001).

  11. 11.

    , , , & Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor. Neuroendocrinology 66, 212–220 (1997).

  12. 12.

    & Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).

  13. 13.

    & Molecular chaperone interactions with steroid receptors: an update. Mol. Endocrinol. 14, 939–946 (2000).

  14. 14.

    et al. Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor. J. Biol. Chem. 278, 4926–4931 (2003).

  15. 15.

    et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

  16. 16.

    & Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Lett. 495, 1–6 (2001).

  17. 17.

    , & A new first step in activation of steroid receptors: hormone–induced switching of FKBP51 and FKBP52 immunophilins. J. Biol. Chem. 277, 4597–4600 (2002).

  18. 18.

    , , , & Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 141, 4107–4113 (2000).

  19. 19.

    et al. Glucocorticoid-resistant B-lymphoblast cell line derived from the Bolivian squirrel monkey (Saimiri boliviensis boliviensis). Lab. Anim. Sci. 48, 364–370 (1998).

  20. 20.

    , , & Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen. Comp. Endocrinol. 124, 152–165 (2001).

  21. 21.

    , , , & Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J. Clin. Endocrinol. Metab. 88, 277–284 (2003).

  22. 22.

    , & The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28, 341–356 (1994).

  23. 23.

    et al. Screening for mental disorders: performance of the Composite International Diagnostic – Screener (CID–S). Int. J. Methods Psychiatr. Res. 8, 59–70 (1999).

  24. 24.

    , , , , & Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study. J. Psychiatr. Res. 35, 83–94 (2001).

  25. 25.

    Statistical Methods for Research Workers (Oliver and Boyd, London, 1932).

  26. 26.

    & Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am. J. Hum. Genet. 75, 424–435 (2004).

  27. 27.

    & The future of association studies: gene-based analysis and replication. Am. J. Hum. Genet. 75, 353–362 (2004).

  28. 28.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  29. 29.

    On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).

  30. 30.

    , , & Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology, 62, 340–347 (1995).

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Acknowledgements

We thank G. Ernst, G. Gajeswski, J. Huber, C. Stallwanger and A. Tontsch for their excellent technical help and Dr. M.E. Keck for helpful discussions. This study was supported in part by the German Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFN) and the Bavarian Ministry of Commerce.

Author information

Affiliations

  1. Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.

    • Elisabeth B Binder
    • , Daria Salyakina
    • , Gabriele M Wochnik
    • , Marcus Ising
    • , Benno Pütz
    • , Shaun Seaman
    • , Susanne Lucae
    • , Martin A Kohli
    • , Thomas Nickel
    • , Heike E Künzel
    • , Brigitte Fuchs
    • , Matthias Majer
    • , Andrea Pfennig
    • , Nikola Kern
    • , Jürgen Brunner
    • , Sieglinde Modell
    • , Tanja Brückl
    • , Nina Müller
    • , Hildegard Pfister
    • , Roselind Lieb
    • , Manfred Uhr
    • , Theo Rein
    • , Florian Holsboer
    •  & Bertram Muller-Myhsok
  2. Institute for Human Genetics, Technical University and GSF-National Research Centre for Environment and Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.

    • Peter Lichtner
    • , Jakob C Mueller
    • , Elin Lõhmussaar
    • , Tim M Strom
    • , Thomas Bettecken
    •  & Thomas Meitinger
  3. Unitat d′Antropologia, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain.

    • Sergi Papiol
  4. Department of Psychiatry, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336 Munich, Germany.

    • Thomas Baghai
    • , Tobias Deiml
    • , Peter Zill
    • , Brigitta Bondy
    •  & Rainer Rupprecht
  5. Bezirkskrankenhaus Augsburg, Dr.-Mack-Straβe 1, 86156 Augsburg, Germany.

    • Thomas Messer
    •  & Oliver Köhnlein
  6. Klinikum Ingolstadt, Krumenauerstraβe 25, 85049 Ingolstadt, Germany.

    • Heike Dabitz

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The authors declare no competing financial interests.

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Correspondence to Elisabeth B Binder.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Information on location of SNPs on the UCSC genome build version hg15, heterozygosity and Hardy-Weinberg equilibrium.

  2. 2.

    Supplementary Table 2

    Association of confounding variables with response to antidepressant treatment and rs1360780 genotype.

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    Supplementary Note

    Assessment of population stratification.

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DOI

https://doi.org/10.1038/ng1479

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