title: Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia.
abstract: BACKGROUND
  Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia.
  
  
  METHODS
  A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions.
  
  
  RESULTS
  In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia.
  
  
  CONCLUSIONS
  This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France; INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France.
authors.forename: Oussama
authors.initials: O
authors.lastname: Kebir
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France; INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Chaumette
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Centre for Biomedical Researh Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Fatjó-Vilas
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Center, Montreal, Quebec H2L 4M1, Canada.
authors.forename: Amirthagowri
authors.initials: A
authors.lastname: Ambalavanan
authors.affiliation: INSERM, U894, Team "Vulnerability of Psychiatric and Addictive Disorders", Centre of Psychiatry and Neurosciences, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ramoz
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Center, Montreal, Quebec H2L 4M1, Canada.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiong
authors.affiliation: INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France; Service de Psychiatrie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Mouaffak
authors.affiliation: INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France; Pôle Hospitalo-Universitaire de Psychiatrie Adulte, CH Guillaume Régnier, Rennes, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Millet
authors.affiliation: Institut de Psychiatrie-GDR 3557 de Psychiatrie, France; Unité de recherche clinique intersectorielle en psychiatrie du Centre Hospitalier Henri Laborit, Poitiers, France; INSERM CIC-P 1402, CHU de Poitiers, France; INSERM U 1084 Experimental and Clinical Neurosciences Laboratory, Université de Poitiers, France.
authors.forename: Nematollah
authors.initials: N
authors.lastname: Jaafari
authors.affiliation: VA Boston Healthcare System, Harvard Medical School, Brockton, MA, USA.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: DeLisi
authors.affiliation: Institut de Psychiatrie-GDR 3557 de Psychiatrie, France; Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Levinson
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Canada.
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
authors.affiliation: Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Centre for Biomedical Researh Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Fañanás
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Center, Montreal, Quebec H2L 4M1, Canada; Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.affiliation: INSERM, U894, Team "Vulnerability of Psychiatric and Addictive Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Louis Mourier, Psychiatry Department, Colombes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubertret
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France; INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France. Electronic address: marie-odile.krebs@inserm.fr.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Krebs
mesh_terms: D015331:Cohort Studies; D004843:Epistasis, Genetic; D005190:Family; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006239:Haplotypes; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D006655:Histone Deacetylases
keywords: Epigenetics; Epistasis; Histone acetylation; Pedigree-based generalized multifactor dimensionality; Psychosis; Tag-SNP