Interaction of FKBP5 Gene Variants and Adverse Life Events in Predicting Depression Onset: Results From a 10-Year Prospective Community Study
Publication: American Journal of Psychiatry
Abstract
Objective:
The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress hormone system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode.
Method:
The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14–24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping.
Results:
While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study.
Conclusions:
These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.
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History
Received: 1 November 2010
Revision received: 12 January 2011
Revision received: 22 February 2011
Accepted: 28 March 2011
Published online: 1 October 2011
Published in print: October 2011
Authors
Funding Information
Dr. Zimmermann has received grant support from the German Federal Ministry of Education and Research. In the past, Dr. Binder has received grant support from Pfizer, Glaxo-Smith-Kline, and NARSAD; currently she receives grant support from NIMH, the Doris Duke Charitable Foundation, the Behrens-Weise Foundation, the NeuroNova AG Foundation, and PharmaNeuroboost; she is also co-inventor on the following patent applications: “FKBP5: a novel target for antidepressant therapy” (international publication number WO 2005/054500) and “Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments” (international application number PCT/EP2005/005194). Dr. Uhr is co-inventor on the following patent applications: “FKBP5: a novel target for antidepressant therapy” (international publication number WO 2005/054500) and “Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments” (international application number: PCT/EP2005/005194). Dr. Lieb has received grant support from the German Federal Ministry of Education and Research and has received speakers honoraria from Wyeth. Dr. Holsboer receives grant support from the German Federal Ministry of Education and Research and is founder/shareholder of Affectis Pharmaceuticals; he is also owner of several patents related to depression. Dr. Ising has received grant support from the German Federal Ministry of Education and Research. Dr. Brückl, Dr. Nocon, Ms. Pfister, Dr. Moffitt, and Dr. Caspi report no financial relationships with commercial interests.Supported by the German Federal Ministry of Education and Research through funding for the Early Developmental Stages of Psychopathology (EDSP) investigation (projects 01EB9405/6, 01EB9901/6, EB01016200, 01EB0140, and 01EB0440) and for the genetic part of the study (project 01GS0481); by Deutsche Forschungsgemeinschaft funding of part of the fieldwork and analyses (grants LA1148/1-1, WI2246/1-1, WI709/7-1, and WI709/8-1); by U.K. Medical Research Council funding of the Dunedin and E-Risk Studies (G9806489, G0100527, G0601483, G1002190); by NIMH (MH-077874); by the National Institute on Aging (AG-032282); and by the New Zealand Health Research Council.
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