Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study.

doi:10.1176/APPI.AJP.2011.10111577

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Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study.

Journal Article•DOI•

Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study.

Petra Zimmermann¹, Tanja Brückl¹, Agnes Nocon¹, Hildegard Pfister¹, Elisabeth B. Binder¹, Manfred Uhr¹, Roselind Lieb¹, Terrie E. Moffitt, Avshalom Caspi, Florian Holsboer¹, Marcus Ising¹ - Show less +7 more•Institutions (1)

Max Planck Society¹

01 Oct 2011-American Journal of Psychiatry (NIH Public Access)-Vol. 168, Iss: 10, pp 1107-1116

TL;DR: These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression, with the strongest effect for severe trauma.

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Abstract: The FKBP5 gene modulates function of glucocorticoid receptors and has been frequently studied as a risk factor for depression and suicidality. This long-term study found a gene-by-environment effect for minor variants in the gene in the presence of trauma but not deprivation.

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Journal Article•DOI•

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions

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Torsten Klengel¹, Divya Mehta¹, Christoph Anacker², Monika Rex-Haffner¹, Jens C. Pruessner³, Carmine M. Pariante², Thaddeus W.W. Pace⁴, Kristina B. Mercer⁵, Helen S. Mayberg⁴, Bekh Bradley⁶, Bekh Bradley⁴, Charles B. Nemeroff⁷, Florian Holsboer¹, Christine Heim⁴, Christine Heim⁸, Kerry J. Ressler⁴, Kerry J. Ressler⁵, Theo Rein¹, Elisabeth B. Binder¹ - Show less +15 more•Institutions (8)

Max Planck Society¹, King's College London², McGill University³, Emory University⁴, Howard Hughes Medical Institute⁵, Veterans Health Administration⁶, University of Miami⁷, Charité⁸

01 Jan 2013-Nature Neuroscience

TL;DR: It is found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 gene increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5.

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Abstract: Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

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1,177 citations

Journal Article•DOI•

The Biological Effects of Childhood Trauma

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Michael D. De Bellis¹, Abigail Zisk¹•Institutions (1)

Duke University¹

01 Apr 2014-Child and Adolescent Psychiatric Clinics of North America

TL;DR: This article focuses on peer-reviewed literature on the neurobiological sequelae of childhood trauma in children and in adults with histories of Childhood trauma.

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572 citations

Cites background from "Interaction of FKBP5 gene variants ..."

...study, 884Caucasianswith no history of depressionwere enrolled at age 12 to 14 years and followed for 10 years.(92) Thosewhowere homozygous for theminor alleles and had traumatic (but not separation [i....
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Journal Article•DOI•

Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect

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Charles B. Nemeroff¹•Institutions (1)

University of Miami¹

02 Mar 2016-Neuron

TL;DR: This Review summarizes many of the persistent biological alterations associated with childhood maltreatment including changes in neuroendocrine and neurotransmitter systems and pro-inflammatory cytokines in addition to specific alterations in brain areas associated with mood regulation.

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527 citations

Cites background from "Interaction of FKBP5 gene variants ..."

..., 2010)—individuals homozygous for the minor alleles are particularly sensitive to the depressogenic effects of trauma (Zimmermann et al., 2011) and also interact with childhood trauma to increase suicide attempts (Roy et al....
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...…these findings (Xie et al., 2010)—individuals homozygous for the minor alleles are particularly sensitive to the depressogenic effects of trauma (Zimmermann et al., 2011) and also interact with childhood trauma to increase suicide attempts (Roy et al., 2010), as well as increase aggressive…...
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Journal Article•DOI•

The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications.

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Steven Moylan¹, Michael Maes, Naomi R. Wray², Michael Berk•Institutions (2)

Deakin University¹, University of Queensland²

01 May 2013-Molecular Psychiatry

TL;DR: Current knowledge of the neuroprogressive processes that may occur in MDD is reviewed, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation.

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Abstract: In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.

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443 citations

Journal Article•DOI•

Gene-Stress-Epigenetic Regulation of FKBP5: Clinical and Translational Implications.

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Anthony S. Zannas¹, Anthony S. Zannas², Tobias Wiechmann², Nils C. Gassen², Elisabeth B. Binder³, Elisabeth B. Binder² - Show less +2 more•Institutions (3)

Duke University¹, Max Planck Society², Emory University³

01 Jan 2016-Neuropsychopharmacology

TL;DR: The findings related to FKBP5 illustrate how a deeper understanding of the molecular and systemic mechanisms underlying specific gene–environment interactions may provide insights into the pathogenesis of stress-related disorders.

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360 citations

Cites background from "Interaction of FKBP5 gene variants ..."

...…et al (2011) 2144 Caucasian Depression (BDI-II) CTQ rs1360780 T p= 0.006 The T allele interacted with childhood abuse to increase MDD risk Zimmermann et al (2011) 884 (discovery sample), 1037 (Dunedin study replication sample), and 1116 (E-Risk study replication sample) All subjects…...
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...…in carriers of the haplotype associated with higher FKBP5 mRNA induction increases the risk for psychiatric disorders in adulthood (Appel et al, 2011; Binder et al, 2008; Dackis et al, 2012; Lessard and Holman, 2014; Roy et al, 2010; Roy et al, 2012; Xie et al, 2010; Zimmermann et al, 2011)....
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...…examined to date include MDD or depressive symptoms (Appel et al, 2011; Dackis et al, 2012; Kohrt et al, 2015; VanZomeren-Dohm et al, 2015; Zimmermann et al, 2011), PTSD and related phenotypes (Binder et al, 2008; Boscarino et al, 2012; Klengel and Binder, 2013a; Koenen et al, 2005; Xie…...
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...…have been observed in some studies with traumatic events occurring beyond childhood, in adolescence and early adulthood (Lessard and Holman, 2014; Zimmermann et al, 2011), other studies found that FKBP5–stress interactions are triggered only by childhood trauma (Binder et al, 2008; Klengel et…...
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Patent•

Polymorphisms in abcb1 associated with a lack of clinical response to medicaments

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Manfred Uhr, Florian Holsboer, Bertram Müller-Myhsok

12 Jun 2008

TL;DR: In this article, the authors present methods, compositions, kits and reagents for determining the prognosis of a clinical response in a human patient to a medicament which acts in the central nervous system (CNS) and which is a substrate of the ABCB1 protein.

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Abstract: The present invention relates to methods, compositions, kits and reagents for determining the prognosis of a clinical response in a human patient to a medicament which acts in the central nervous system (CNS) and which is a substrate of the ABCB1 protein. Further, the invention relates to a combination of medicaments for the treatment of human patients having specific polymorphisms in the ABCB1 gene.

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28 citations