title: The role of hypothalamus-pituitary-adrenal genes and childhood trauma in borderline personality disorder.
abstract: Current knowledge suggests that borderline personality disorder (BPD) results from the interaction between genetic and environmental factors. Research has mainly focused on monoaminergic genetic variants and their modulation by traumatic events, especially those occurring during childhood. However, to the best of our knowledge, there are no studies on the genetics of hypothalamus-pituitary-adrenal (HPA) axis, despite its vulnerability to early stress and its involvement in BPD pathogenesis. The aim of this study was to investigate the contribution of genetic variants in the HPA axis and to explore the modulating effect of childhood trauma in a large sample of BPD patients and controls. DNA was obtained from a sample of 481 subjects with BPD and 442 controls. Case-control differences in allelic frequencies of 47 polymorphisms in 10 HPA axis genes were analysed. Modulation of genetic associations by the presence of childhood trauma was also investigated by dividing the sample into three groups: BPD with trauma, BPD without trauma and controls. Two FKBP5 polymorphisms (rs4713902-C and rs9470079-A) showed significant associations with BPD. There were also associations between BPD and haplotype combinations of the genes FKBP5 and CRHR1. Two FKBP5 alleles (rs3798347-T and rs10947563-A) were more frequent in BPD subjects with history of physical abuse and emotional neglect and two CRHR2 variants (rs4722999-C and rs12701020-C) in BPD subjects with sexual and physical abuse. Our findings suggest a contribution of HPA axis genetic variants to BPD pathogenesis and reinforce the hypothesis of the modulating effect of childhood trauma in the development of this disorder.
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martín-Blanco
authors.affiliation: Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Paseo de la Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Soler
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Fundació Docència i Recerca Mutua Terrassa, St. Antoni 19, 08221, Terrassa, Barcelona, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Arranz
authors.affiliation: Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.|Department of Psychiatry and Mental Health, Consorci Sanitari de l'Anoia, Avenida Catalunya 11, Igualada, 08700, Barcelona, Spain.|Institut of Neurosciences, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vega
authors.affiliation: Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Paseo de la Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Calvo
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Elices
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institut, Hospital Universitari Vall d'Hebron, Paseo de la Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanchez-Mora
authors.affiliation: Psychiatric Genetics Unit, Vall d'Hebron Research Institut, Hospital Universitari Vall d'Hebron, Paseo de la Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Iris
authors.initials: I
authors.lastname: García-Martinez
authors.affiliation: Genetics Department, Hospital de la Santa Creu i Sant Pau, U705, CIBERER, Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.
authors.forename: Juliana
authors.initials: J
authors.lastname: Salazar
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Carmona
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Bauzà
authors.affiliation: Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.|Department of Psychiatry, Hospital Universitari Vall d'Hebron, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Paseo de la Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Prat
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez
authors.affiliation: Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut d'Investigació Biomèdica - Sant Pau (IIB-Sant Pau), Av. Sant Antoni Mª Claret 167, 08025, Barcelona, Spain. jpascual@santpau.cat.|Psychiatry and Legal Medicine Department, Universitat Autònoma de Barcelona, Campus de la UAB, Plaza Cívica, s/n, Bellaterra, 08193, Barcelona, Spain. jpascual@santpau.cat.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Pascual
mesh_terms: D000328:Adult; D001883:Borderline Personality Disorder / Q000209:etiology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002649:Child Abuse / Q000523:psychology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D055815:Young Adult; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
keywords: Borderline personality disorder; Childhood trauma; Etiology; Genetics; Hypothalamus–pituitary–adrenal (HPA) axis; Polymorphisms