Nature Genetics
36, 1319 - 1325 (2004)
Published online: 21 November 2004; | doi:10.1038/ng1479
Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatmentElisabeth B Binder1, Daria Salyakina1, Peter Lichtner2, Gabriele M Wochnik1, Marcus Ising1, Benno Pütz1, Sergi Papiol3, Shaun Seaman1, Susanne Lucae1, Martin A Kohli1, Thomas Nickel1, Heike E Künzel1, Brigitte Fuchs1, Matthias Majer1, Andrea Pfennig1, Nikola Kern1, Jürgen Brunner1, Sieglinde Modell1, Thomas Baghai4, Tobias Deiml4, Peter Zill4, Brigitta Bondy4, Rainer Rupprecht4, Thomas Messer5, Oliver Köhnlein5, Heike Dabitz6, Tanja Brückl1, Nina Müller1, Hildegard Pfister1, Roselind Lieb1, Jakob C Mueller2, Elin Lõhmussaar2, Tim M Strom2, Thomas Bettecken2, Thomas Meitinger2, Manfred Uhr1, Theo Rein1, Florian Holsboer1
& Bertram Muller-Myhsok11
Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. 2
Institute for Human Genetics, Technical University and GSF-National Research Centre for Environment and Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. 3
Unitat d'Antropologia, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. 4
Department of Psychiatry, Ludwig-Maximilians-University Munich, Nussbaumstrasse 7, 80336 Munich, Germany. 5
Bezirkskrankenhaus Augsburg, Dr.-Mack-Stra e 1, 86156 Augsburg, Germany. 6
Klinikum Ingolstadt, Krumenauerstrae 25, 85049 Ingolstadt, Germany.
Correspondence should be addressed to Elisabeth B Binder ebinder@genetics.emory.eduThe 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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