International Journal of Neuropsychopharmacology (2010), 13, 649–660. Copyright f CINP 2010 doi:10.1017/S1461145709991155
ARTICLE
DNA sequence variants of the FKBP5 gene are associated with unipolar depression Astrid Zobel1, Anna Schuhmacher1, Frank Jessen1, Susanne Ho¨fels1, Olrik von Widdern1, Martin Metten1, Ute Pfeiffer1, Claudia Hanses1, Tim Becker2, Marcella Rietschel1,3, Lukas Scheef4, Wolfgang Block4, Hans H. Schild4, Wolfgang Maier1 and Sibylle G. Schwab1,5 1
Department of Psychiatry, University of Bonn, Germany Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany 3 Central Institute of Mental Health, Division of Genetic Epidemiology in Psychiatry, Mannheim, University of Heidelberg, Germany 4 Department of Radiology, University of Bonn, Germany 5 Western Australian Institute for Medical Research and Centre for Medical Research, School of Medicine and Pharmacology, and School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia 2
Abstract FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic–pituitary–adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/ CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume. Received 26 May 2009 ; Revised 3 November 2009 ; Accepted 22 November 2009 ; First published online 5 January 2010 Key words : Depression-related phenotypes, FKBP5, hippocampus, HPA, unipolar depression.
Introduction FKBP5 belongs to the family of immunophilin class of proteins. It is a co-chaperone of hsp-90 and, as such, is involved in the regulation of the hypothalamic– pituitary–adrenal (HPA) system through adaptive Address for correspondence : A. Zobel, M.D., M.B.A., Department of Psychiatry, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany. Tel. : 049 (0)228-287 15717 Fax : 049 (0)228-287 14760 Email :
[email protected]
changes in the glucocorticoid receptor (GR). The HPA system is regarded as a playing a major role in response to stress (Park et al. 2007). It is dysregulated in stress-associated disorders as during depressive episodes, and there is strong evidence that normalization of HPA activity is a prerequisite for sustaining remission (Holsboer-Trachsler et al. 1991 ; Zobel et al. 2001). Consequently, factors involved in regulating the HPA system are also thought to play a major role in development and relief of depressive episodes. Two lines of evidence were used to implicate FKBP5 in
A. Zobel et al.
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chr6 (p21,31)
11 10 9 8 7 6
12 13
q21
54
3 2
27
1
3’
5’
Location of SNPs rs3800373 rs7555658
rs1360780 rs1334894
rs4713916
Fig. 1. Genomic structure of the FKBP5 gene.
response to antidepressants : (a) consistent allelic association with response to antidepressant treatment in two independent samples, and (b) functional effects on gene expression for specific implicated alleles (Binder et al. 2004). In a Spanish sample of depressive patients, association of one of these single nucleotide polymorphisms (SNPs) with treatment response using selective serotonin reuptake inhibitors (SSRIs) was shown, but with the opposite allele (Papiol et al. 2007). More recently, association of FKBP5 variants with treatment response was replicated in an independent sample of German depressed patients (Kirchheiner et al. 2008). Binder and colleagues also demonstrated that specific alleles in the FKBP5 gene contribute to the inter-individual variation of recurrence of depressive episodes (Binder et al. 2004). However, Binder and colleagues were unable to support an association with the diagnosis of affective disorders in 294 hospitalized in-patients compared to 339 matched controls after controlling for multiple testing among 12 selected markers and their combinations. Gawlik et al. (2006) selected three markers from the Binder study and investigated association with major affective disorders (more than 70 % of the cases with bipolar disorder) in a German sample. Gawlik and colleagues were unable to show association, even though one rare haplotype displayed a strong difference between both groups and another haplotype was associated with longer duration of the disorder. A more recent analysis of three SNPs selected from the Binder et al. (2004) study was conducted in the STAR*D sample comprising 1809 cases with unipolar depression and 739 DNA controls (from a cell repository) (Lekman et al. 2008). Significant group differences in the frequency distribution of genotypes were detected for two of the selected markers yet the effect sizes were very modest. One of these variants revealed
the same association with clinical response under treatment with citalopram as reported by Binder et al. (2004) This relationship is primarily evident on the level of remission after 14 wk. The reported association was most prominent in the white non-Hispanic population. Genetic associations to other disorders and psychosocial conditions were also reported : to post-traumatic stress disorder by Binder et al. (2008) and to psychosocial stress in healthy volunteers by Ising et al. (2008). Recently, Willour et al. (2009) reported a family-based association of FKBP5 variants with bipolar disorder, thereby corroborating the view that FKBP5 impacts on the risk for affective disorders. The present study exclusively focuses on recurrent unipolar depression, and explores the genetic association with variants in the FKBP5 gene. For this purpose we selected five markers from the region revealing association with treatment response in the study by Binder et al. (2004) (Fig. 1). It has been suggested that heritable biological correlates of the psychopathologically defined diagnoses may be a more suitable phenotype for genetic association studies. Those associated phenotypes have also been identified for unipolar depression (Zobel & Maier, 2004, 2009). The hippocampal volume is of particular interest in this respect as (a) a reduction in volume is consistently found to be associated with unipolar depression (McKinnon et al. 2009 ; Savitz & Drevets, 2009), (b) it is a heritable trait (Frodl et al. 2008 ; Savitz & Drevets, 2009), and (c) many known depression-related pathophysiological pathways are located in or linked to the hippocampus (Balu & Lucki, 2009 ; Savitz & Drevets, 2009). The hippocampal volume was therefore included in our analysis. Another associated phenotype of depression is HPA activity, which can be most specifically measured by the combined dexamethasone/corticotrophin-releasing
FKBP5 gene variants and unipolar depression
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Table 1. Sociodemographic description of the study sample
Age, yr (¡S.D.) Gender male/female, % Age male/female, yr (¡S.D.) Age of onset of the disease, yr (¡S.D.) Total duration of the disease, yr (¡S.D.) Number of previous episodes (¡S.D.) Duration of the longest episode, weeks (¡S.D.)
Cases (n=268)
Controls (n=284)
p
48.92¡14.0 36.6/63.4 49.21¡13.0/48.75¡14.6 35.3¡13.05 11.36¡11.16 3.22¡2.7 34.8¡24.0
46.48¡15.0 40.5/59.5 48.17¡14.6/45.33¡15.2 n.a. n.a n.a n.a
0.06 0.38 0.35
S.D.,
Standard deviation. * 0.01
