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

Binder, Elisabeth B.; Salyakina, Daria; Lichtner, Peter; Wochnik, Gabriela M.; Ising, Marcus; Pütz, Benno; Papiol, Sergi; Seaman, Shaun; Lucae, Susanne; Kohli, Martin; Nickel, Thomas; Künzel, Heike; Fuchs, B.; Majer, Matthias; Pfennig, Andrea; Kern, N.; Brunner, Jürgen; Modell, S.; Baghai, Thomas C.; Deiml, Tobias; Zill, Peter; Bondy, Brigitta; Rupprecht, Rainer; Messer, Thomas; Köhnlein, Oliver; Dabitz, Heike; Brückl, Tanja; Müller, N.; Pfister, Hildegard; Lieb, Roselind; Mueller, Jakob C.; Lõhmussaar, Elin; Strom, Tim M.; Bettecken, Thomas; Meitinger, Thomas; Uhr, Manfred; Rein, Theo; Holsboer, Florian; Müller‐Myhsok, Bertram

doi:10.1038/ng1479

Cited by 874 publications

(796 citation statements)

References 27 publications

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“…This resonates with a recent study showing that, unlike momentary stress, the exposure of early‐life stress may lead to long‐lasting molecular mechanisms in relevant stress‐response systems, shaping individual differential trajectories and resulting in a greater risk for the development of psychopathological outcomes 50. Prior studies have consistently demonstrated that exposure to childhood trauma increases the risk for several stress‐related phenotypes for carriers of the minor alleles (C, A, T, T) of FKBP5 SNPs (rs3800373, rs9296158, rs1360870, and rs9470080; e.g., 51) or for the risk haplotype including these three or four alleles (e.g., 15, 52). Specifically, these risk alleles have been associated with decreased sensitivity of the glucocorticoid receptor (GR) to circulating cortisol, entailing a diminished negative feedback regulation of the HPA axis and hence, enduring responses to stress 51.…”

Section: Discussionmentioning

confidence: 99%

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Cristóbal-Narváez

Sheinbaum

Myin-Germeys

et al. 2017

Acta Psychiatr Scand

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ObjectiveThe interaction of single nucleotide polymorphisms with both distal and proximal environmental factors across the extended psychosis phenotype is understudied. This study examined (i) the interaction of relevant SNPs with both early‐life adversity and proximal (momentary) stress on psychotic experiences (PEs) in an extended psychosis sample; and (ii) differences between early‐psychosis and non‐clinical groups for these interactions.MethodsTwo hundred and forty‐two non‐clinical and 96 early‐psychosis participants were prompted randomly eight times daily for 1 week to complete assessments of current experiences, including PEs and stress. Participants also reported on childhood trauma and were genotyped for 10 SNPs on COMT, RGS4, BDNF, FKBP5, and OXTR genes.ResultsUnlike genetic variants, distal and proximal stressors were associated with PEs in both samples and were more strongly associated with PEs in the early‐psychosis than in the non‐clinical group. The RGS4 TA and FKBP5 CATT haplotypes interacted with distal stress, whereas the A allele of OXTR (rs2254298) interacted with proximal stress, increasing momentary levels of PEs in the early‐psychosis group. No interactions emerged with COMT or BDNF variants.ConclusionIndividual differences in relevant stress‐regulation systems interact with both distal and proximal psychosocial stressors in shaping the daily‐life manifestation of PEs across the psychosis continuum.

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Section: Discussionmentioning

confidence: 99%

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Cristóbal-Narváez

Sheinbaum

Myin-Germeys

et al. 2017

Acta Psychiatr Scand

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“…Other genetic factors may also lead to a dysfunction of the GR. Recently, Binder et al (2004) found that an intronic polymorphism in FKBP5, a GRregulating cochaperone of hsp-90, was highly associated with increased response to antidepressant treatment and postulated a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs. Clearly, the function of the HPA axis and the clinical appearance of MDD are complex phenotypes, influenced by many genes and environmental conditions, most single genes probably accounting for only a small proportion of phenotype variability.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Gene-Based SNP Analysis in Patients with Recurrent Major Depression

West

Eede

Del-Favero

et al. 2005

Neuropsychopharmacol

136

108

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Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p ¼ 0.02) and genotype (p ¼ 0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p ¼ 0.02) and genotype (p ¼ 0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5 0 region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5 0 region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

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“…The cortisol signaling cascade is complex and involves numerous chaperones, accessory proteins, co-regulators and interacting transcription factors that permit differentiation between the MR-and GR-mediated actions (De Bosscher et al, 2003;Pascual-Le Tallec and Lombes, 2005). For instance, recently it was found that increase in recurrence of depressive episodes is associated with a variant in a gene (FKBP5) that regulates GR activity (Binder et al, 2004). Therefore, not only genes directly involved in stress-induced signaling pathways, but genes regulating their activity also appear to be involved in the development of these disorders, and their actions should be analyzed in more detail.…”

Section: Discussionmentioning

confidence: 99%

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

Kuningas

Rijk

Westendorp

et al. 2006

Neuropsychopharmacol

118

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Depression and cognitive decline have been associated with changes in circulating cortisol concentrations. Cortisol exerts its functions through mineralocorticoid (MR) and glucocorticoid (GR) receptors. However, data on the influence of variations in the MR and GR genes on depressive symptoms and cognitive functioning in older adults are scarce. Therefore, we explored the impact of MR-215G/C, MR-I180V, GR-ER22/23EK, GR-N363S, and GR-BclI polymorphisms on these end points in the population-based Leiden 85-plus Study. This prospective study includes 563 participants aged 85 years and older, with a mean follow-up of 4.2 years. In this study, high morning cortisol levels (per 1 SD cortisol) associated with impairments in global cognitive functioning (p ¼ 0.002) at baseline (age 85). These impairments were mainly attributable to lower attention (p ¼ 0.057) and slower processing speed (p ¼ 0.014). Similar effects were also observed during follow-up (age 85-90), where participants with higher cortisol levels (per 1 SD cortisol) had impaired global cognitive functioning (p ¼ 0.003), as well as impairments in attention (p ¼ 0.034) and processing speed (p ¼ 0.013). Changes in depressive symptoms were observed for the MR-I180V single-nucleotide polymorphism (SNP), where during follow-up the prevalence of depressive symptoms was higher in the 180V-allele carriers (p ¼ 0.049) compared to noncarriers. Dependent on these polymorphisms, no differences in overall and in specific domains of cognitive functioning were observed. In conclusion, the MR-I180V SNP has a specific effect on depressive symptoms, independent from cognitive functioning, and other polymorphisms in the MR and GR genes. In contrast, these genetic variants in the MR and GR genes do not influence cognitive functioning in old age.

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

Cited by 874 publications

References 27 publications

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Glucocorticoid Receptor Gene-Based SNP Analysis in Patients with Recurrent Major Depression

Mental Performance in Old Age Dependent on Cortisol and Genetic Variance in the Mineralocorticoid and Glucocorticoid Receptors

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