DNA sequence variants of the FKBP5 gene are associated with unipolar depression

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.

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

“…Similarly, elevated glucocorticoid levels have been associated with larger amygdala volumes (Buss et al 2012;Lupien et al 2011). Considering a heightened amygdala response and a larger volume as possible endophenotypes for stress-related disorders, the present findings are in line with previous reports suggesting an important role of the FKBP5 T allele in mood disorders (Appel et al 2011;Binder et al 2004;Lavebratt et al 2010;Lekman et al 2008;Zobel et al 2010) and PTSD (Binder et al 2008).…”

“…Indeed, T homozygotes were found to exhibit elevated cortisol levels during recovery after stress (Ising et al 2008). In line with this, rs1360780 has been associated with psychopathology such as mood disorders (Binder et al 2004;Lavebratt et al 2010;Lekman et al 2008;Zobel et al 2010) and suicidality (Brent et al 2010). Moreover, this SNP has been shown to interact with childhood abuse in predicting PTSD symptoms (Binder et al 2008) and susceptibility to depression (Appel et al 2011), with an increased risk in the TT genotype following childhood abuse.…”

“…Emotional neglect was assessed retrospectively using a subscale of the Childhood Trauma Questionnaire (CTQ, Bernstein et al 2003). In addition to the effect on amygdala activity, FKBP5 has been related to increased hippocampal activity as well as to differences in hippocampal shape (Fani et al 2013), volume (Zobel et al 2010) and volume change with behavioral trauma treatment (Levy-Gigi et al 2013). No study, so far, has investigated the impact of FKBP5 on amygdala volume.…”

Elucidating Molecular Networks That Either Affect or Respond to Plasma Cortisol Concentration in Target Tissues of Liver and Muscle

“…The identified candidate genes associated with cortisol concentrations may enhance discovery of genes associated with immune, metabolic, and behavioral traits in humans. Similar studies have identified candidate genes associated with cortisol concentrations that are also causally associated with depression (Gottesman and Gould 2003;Zobel et al 2010;Velders et al 2011).…”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…The rs1360780 T allele was identified as the risk allele by three studies, the rs9470080 T allele by two studies, and the rs3800373 C allele by one study (Zannas and Binder 2014). Some studies did not take into account FKBP5 environment interactions and three studies found that the rs1360780 T allele was associated with increased risk of depression (Lekman et al 2008;Lavebratt et al 2010;Szczepankiewicz et al 2014), two studies found an effect of rs4713916 (Zobel et al 2010;Szczepankiewicz et al 2014), and non-replicated findings were reported for rs9470080, rs9296158 (Szczepankiewicz et al 2014) and rs3800373 (Zobel et al 2010).…”