title: Implication of NOTCH1 gene in susceptibility to anxiety and depression among sexual abuse victims.
abstract: Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR=2.21, q=0.043) and rs3013302 (OR=2.15, q=0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders.
authors.affiliation: Department of Psychology, University of California, Berkeley, Berkeley, CA, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Steine
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Zayats
authors.affiliation: Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.|Genomics Core Facility, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: C
authors.initials: C
authors.lastname: Stansberg
authors.affiliation: Department of Psychosocial Science, University of Bergen, Bergen, Norway.|Norwegian Competence Center of Sleep Disorders, Haukeland University Hospital, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Pallesen
authors.affiliation: Norwegian Competence Center of Sleep Disorders, Haukeland University Hospital, Bergen, Norway.|Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Mrdalj
authors.affiliation: The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, Haukeland University Hospital, Bergen, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Håvik
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.|Department of Biology, University of Bergen, Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Soulé
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.|Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.|Regional Centre for Child and Youth Mental Health and Child Welfare, Bergen, Norway.
authors.forename: A M
authors.initials: AM
authors.lastname: Milde
authors.affiliation: The Norwegian Centre for Mental Disorders Research (NORMENT) and the K.G. Jebsen Centre for Psychosis Research, Department of Clinical Science, Haukeland University Hospital, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Skrede
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Murison
authors.affiliation: Clinical Neuroscience Division, VA National Center for PTSD, West Haven, CT, USA.|Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Krystal
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.|Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Grønli
mesh_terms: D000483:Alleles; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D003866:Depressive Disorder / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008016:Life Change Events; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000235:genetics*; D012742:Sex Offenses / Q000523:psychology*; D057170:Translational Research, Biomedical
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1