title: Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders.
abstract: Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
authors.affiliation: School of Psychology, University of Sussex, Brighton, UK.|King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Lester
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Jonathan R I
authors.initials: JR
authors.lastname: Coleman
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Roberts
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Keers
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.|National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, Beckenham, UK.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Research Institute Child Development and Education, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Bögels
authors.affiliation: School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK.
authors.forename: Cathy
authors.initials: C
authors.lastname: Creswell
authors.affiliation: Department of Psychology, Centre for Emotional Health, Macquarie University, Sydney, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hudson
authors.affiliation: Department of Psychology, Centre for Emotional Health, Macquarie University, Sydney, Australia.|MRC Cognition and Brain Sciences Unit, Cambridge, UK.|Brain and Mind Research Institute, University of Sydney, Sydney, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: McKinnon
authors.affiliation: Department of Clinical Psychology and Experimental Psychopathology, University of Groningen, Groningen, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Nauta
authors.affiliation: Department of Psychology, Centre for Emotional Health, Macquarie University, Sydney, Australia.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Rapee
authors.affiliation: Department of Psychology, Ruhr-Universität Bochum, Bochum, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Yale University School of Medicine, Child Study Center, New Haven, Connecticut.
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, Reading, UK.
authors.forename: Polly
authors.initials: P
authors.lastname: Waite
authors.affiliation: Department of Child and Adolescent Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: Gro Janne H
authors.initials: GJ
authors.lastname: Wergeland
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
authors.forename: Thalia C
authors.initials: TC
authors.lastname: Eley
mesh_terms: D000293:Adolescent; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D001007:Anxiety / Q000235:genetics; D001008:Anxiety Disorders / Q000235:genetics*; D002648:Child; D015928:Cognitive Behavioral Therapy / Q000379:methods; D063388:Endocannabinoids / Q000235:genetics* / Q000378:metabolism; D005239:Fear / Q000523:psychology; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C571130:CNR1 protein, human; C588309:CNR2 protein, human
keywords: Cognitive Behavior Therapy; anxiety; children; endocannabinoids; fear extinction