Oussama Kebir1, Boris Chaumette1, Mar Fatjó-Vilas2, Amirthagowri Ambalavanan3, Nicolas Ramoz4, Lan Xiong3, Fayçal Mouaffak5, Bruno Millet6, Nematollah Jaafari7, Lynn E DeLisi8, Douglas Levinson9, Ridha Joober10, Lourdes Fañanás2, Guy Rouleau11, Caroline Dubertret12, Marie-Odile Krebs13. 1. 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. 2. 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. 3. Centre of Excellence in Neuromics of Université de Montréal, CHUM Research Center, Montreal, Quebec H2L 4M1, Canada. 4. INSERM, U894, Team "Vulnerability of Psychiatric and Addictive Disorders", Centre of Psychiatry and Neurosciences, Paris, France. 5. 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. 6. 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. 7. 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. 8. VA Boston Healthcare System, Harvard Medical School, Brockton, MA, USA. 9. Institut de Psychiatrie-GDR 3557 de Psychiatrie, France; Stanford University School of Medicine, Stanford, CA, USA. 10. Department of Psychiatry, McGill University, Montreal, Canada. 11. 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. 12. 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. 13. 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.
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. CONCLUSION: 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.
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. CONCLUSION: 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: Dale T Bryant; Christian Landles; Aikaterini S Papadopoulou; Agnesska C Benjamin; Joshua K Duckworth; Thomas Rosahl; Caroline L Benn; Gillian P Bates Journal: Sci Rep Date: 2017-09-19 Impact factor: 4.379
Authors: Soichiro Nakahara; Sarah Medland; Jessica A Turner; Vince D Calhoun; Kelvin O Lim; Bryon A Mueller; Juan R Bustillo; Daniel S O'Leary; Jatin G Vaidya; Sarah McEwen; James Voyvodic; Aysenil Belger; Daniel H Mathalon; Judith M Ford; Guia Guffanti; Fabio Macciardi; Steven G Potkin; Theo G M van Erp Journal: Schizophr Res Date: 2018-06-12 Impact factor: 4.939