Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. 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.

[1]  F. Holsboer,et al.  Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. a prospective study. , 2001, Journal of psychiatric research.

[2]  M. Höfler,et al.  Screening for mental disorders: performance of the Composite International Diagnostic – Screener (CID–S) , 1999 .

[3]  Florian Holsboer,et al.  The Corticosteroid Receptor Hypothesis of Depression , 2000, Neuropsychopharmacology.

[4]  C. Nemeroff,et al.  Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. , 1988, Archives of general psychiatry.

[5]  Jason C. Young,et al.  Essential Role of the Unusual DNA-binding Motif of BAG-1 for Inhibition of the Glucocorticoid Receptor* 210 , 2003, The Journal of Biological Chemistry.

[6]  D. Swaab,et al.  Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. , 1996, Archives of general psychiatry.

[7]  R. Fisher.  Statistical methods for research workers , 1927, Protoplasma.

[8]  I. Heuser,et al.  The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. , 1994, Journal of psychiatric research.

[9]  E. R. Sánchez,et al.  A New First Step in Activation of Steroid Receptors , 2002, The Journal of Biological Chemistry.

[10]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[11]  C. Schiene‐Fischer,et al.  Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases , 2001, FEBS letters.

[12]  F. Holsboer,et al.  Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. , 1995, Neuroendocrinology.

[13]  F. Holsboer,et al.  Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1 , 1998, Nature Genetics.

[14]  J. Scammell,et al.  Glucocorticoid-resistant B-lymphoblast cell line derived from the Bolivian squirrel monkey (Saimiri boliviensis boliviensis). , 1998, Laboratory animal science.

[15]  K. Johnson.  An Update. , 1984, Journal of food protection.

[16]  C. Kilts,et al.  Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. , 1984, Science.

[17]  D. F. Smith,et al.  Molecular chaperone interactions with steroid receptors: an update. , 2000, Molecular endocrinology.

[18]  David F Smith,et al.  Squirrel Monkey Immunophilin FKBP51 Is a Potent Inhibitor of Glucocorticoid Receptor Binding* * This work was supported by Grants 13200 and 01254 from the National Center for Research Resources (to J.G.S.) and NIH Grant DK48218 (to D.F.S.). , 2000, Endocrinology.

[19]  Frank Dudbridge,et al.  Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. , 2004, American journal of human genetics.

[20]  P. Sham,et al.  The future of association studies: gene-based analysis and replication. , 2004, American journal of human genetics.

[21]  R. Fisher,et al.  Statistical Methods for Research Workers , 1930, Nature.

[22]  F. Holsboer,et al.  Antidepressants and hypothalamic-pituitary-adrenocortical regulation. , 1996, Endocrine reviews.

[23]  Bart van der Burg,et al.  Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  C. Nemeroff.  The Role of Corticotropin-Releasing Factor in the Pathogenesis of Major Depression , 1988, Pharmacopsychiatry.

[25]  W. Pratt,et al.  Steroid receptor interactions with heat shock protein and immunophilin chaperones. , 1997, Endocrine reviews.

[26]  Michael J. Owens,et al.  Treatment of mood disorders , 2002, Nature Neuroscience.

[27]  R. Lewontin,et al.  On measures of gametic disequilibrium. , 1988, Genetics.

[28]  F. Holsboer,et al.  Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress , 2003, Nature Neuroscience.

[29]  S. Gabriel,et al.  Assessing the impact of population stratification on genetic association studies , 2004, Nature Genetics.

[30]  Carmine M Pariante,et al.  Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment , 2001, Biological Psychiatry.

[31]  F. Holsboer,et al.  Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor. , 1997, Neuroendocrinology.

[32]  D. F. Smith,et al.  Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. , 2001, General and comparative endocrinology.