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

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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Figure 1: LD structure of the FKBP5 region and association of SNPs in this region with response to antidepressants.
Figure 2: Association of rs1360780 and response over the first 5 weeks of antidepressant treatment.
Figure 3: Number of previous depressive episodes and rs1360780 genotype.
Figure 4: Association of rs1360780 genotypes and FKBP5 protein and mRNA levels.
Figure 5: Association of rs1360780 genotype and neuroendocrine measures in depressed individuals.

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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.

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Correspondence to Elisabeth B Binder.

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Supplementary information

Supplementary Table 1

Information on location of SNPs on the UCSC genome build version hg15, heterozygosity and Hardy-Weinberg equilibrium. (PDF 17 kb)

Supplementary Table 2

Association of confounding variables with response to antidepressant treatment and rs1360780 genotype. (PDF 4 kb)

Supplementary Note

Assessment of population stratification. (PDF 20 kb)

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Binder, E., Salyakina, D., Lichtner, P. et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36, 1319–1325 (2004). https://doi.org/10.1038/ng1479

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