title: HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS.
abstract: BACKGROUND
  Hypothalamic-pituitary-adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).
  
  
  METHODS
  Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).
  
  
  RESULTS
  Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.
  
  
  CONCLUSIONS
  Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Susanna
authors.initials: S
authors.lastname: Roberts
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Keers
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.|School of Psychology, University of Sussex, United Kingdom.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Lester
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Jonathan R I
authors.initials: JR
authors.lastname: Coleman
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.|National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, United Kingdom.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Psychology and Behavioural Sciences, Aarhus University, Aarhus, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Arendt
authors.affiliation: Department of Psychology, University of Basel, Basel, Switzerland.
authors.forename: Judith
authors.initials: J
authors.lastname: Blatter-Meunier
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, United Kingdom.|Department of Psychology, Stellenbosch University, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Cooper
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, United Kingdom.
authors.forename: Cathy
authors.initials: C
authors.lastname: Creswell
authors.affiliation: Anxiety Disorders Research Network, Haukeland University Hospital, Bergen, Norway.
authors.forename: Krister
authors.initials: K
authors.lastname: Fjermestad
authors.affiliation: Anxiety Disorders Research Network, Haukeland University Hospital, Bergen, Norway.
authors.forename: Odd E
authors.initials: OE
authors.lastname: Havik
authors.affiliation: Department of Forensic Psychiatry, University of Basel Psychiatric Clinics, Basel, Switzerland.
authors.forename: Chantal
authors.initials: C
authors.lastname: Herren
authors.affiliation: Department of Child and Adolescent Psychiatry/De Bascule, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Sanne M
authors.initials: SM
authors.lastname: Hogendoorn
authors.affiliation: Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hudson
authors.affiliation: Department of Psychology, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Krause
authors.affiliation: Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Lyneham
authors.affiliation: Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia.
authors.forename: Talia
authors.initials: T
authors.lastname: Morris
authors.affiliation: Department of Clinical Psychology and Experimental Psychopathology, University of Groningen, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nauta
authors.affiliation: Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Rapee
authors.affiliation: Child Anxiety and Phobia Program, Department of Psychology, Florida International University, Miami, USA.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rey
authors.affiliation: Department of Psychology, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Centre for Emotional Health, Department of Psychology, Macquarie University, Sydney, Australia.
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Schneider
authors.affiliation: Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Silverman
authors.affiliation: Department of Psychology and Behavioural Sciences, Aarhus University, Aarhus, Denmark.
authors.forename: Mikael
authors.initials: M
authors.lastname: Thastum
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, United Kingdom.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Thirlwall
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, United Kingdom.
authors.forename: Polly
authors.initials: P
authors.lastname: Waite
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Thalia C
authors.initials: TC
authors.lastname: Eley
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Chloe C Y
authors.initials: CC
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000483:Alleles; D001008:Anxiety Disorders / Q000235:genetics* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D015928:Cognitive Behavioral Therapy; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D057890:Epigenomics; D005260:Female; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D016896:Treatment Outcome; D000099159:Tacrolimus Binding Protein 5
chemical_list: D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C497713:NR3C1 protein, human
keywords: DNA methylation; FKBP5; HPA axis; anxiety; biological markers; child/adolescent; cognitive behavior therapy; genetics; glucocorticoid receptor; therapygenetics; treatment