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Evidence Mounting for Gene-by-Environment Interactions at the FKBP5 Locus Predicting Psychiatric Symptoms

  • Thorhildur Halldorsdottir
    Correspondence
    Address correspondence to: Thorhildur Halldorsdottir, Ph.D., Max-Planck-Institut fur Psychiatrie, Department of Translational Research in Psychiatry, Kraepelinstrasse 2-10, Munich 80804, Germany; .
    Affiliations
    Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
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Published:September 07, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.09.001
      Gene variants moderating the stress response and the regulation of the hypothalamic-pituitary-adrenal axis have proven to be among the most promising candidates for gene-by-environment interaction (G×E) studies in stress-related disorders. Among these genes, the FK506-binding protein 5 (FKBP5) gene, a central effector on glucocorticoid receptor sensitivity and stress responsivity, is one of the most comprehensively studied (
      • Binder E.B.
      The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders.
      ). In 2008, Binder et al. (
      • Binder E.B.
      • Bradley R.G.
      • Liu W.
      • Epstein M.P.
      • Deveau T.C.
      • Mercer K.B.
      • et al.
      Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults.
      ) were the first to report on FKBP5’s moderating effect on childhood trauma and posttraumatic stress disorder symptoms. Since then, this interaction between FKBP5 and environmental stressors has been found to alter the risk for a range of psychiatric problems, including depression, suicide attempts, aggression, and psychosis in a large number of ethnically diverse studies including over 12,000 individuals (
      • Zannas A.S.
      • Wiechmann T.
      • Gassen N.C.
      • Binder E.B.
      Gene-stress-epigenetic regulation of FKBP5: Clinical and translational implications.
      ). Collectively, these studies have shown that the alleles associated with higher FKBP5 induction increase an individual’s susceptibility toward diverse disease phenotypes following exposure to environmental stressors. In addition to these genetic association studies, evidence for FKBP5 moderating the relationship between environmental stressors and psychopathology has been validated with corroborating molecular, endocrine, and neuroimaging findings (
      • Zannas A.S.
      • Wiechmann T.
      • Gassen N.C.
      • Binder E.B.
      Gene-stress-epigenetic regulation of FKBP5: Clinical and translational implications.
      ).
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