title: BDNF rs6265 methylation and genotype interact on risk for schizophrenia.
abstract: Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.|b Lieber Institute for Brain Development, Johns Hopkins University Medical Campus , Baltimore , MD , US.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.affiliation: c Department of Clinical and Community Sciences, Università degli Studi di Milano , Milan , Italy.|d Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Maggiore Hospital, Mangiagalli and Regina Elena Foundation , Milan , Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cavalleri
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.affiliation: e Istituto di Endocrinologia e Oncologia Sperimentale, IEOS, CNR, and Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli 'Federico II' , Naples.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Angrisano
authors.affiliation: f Department of Physiology and Pharmacology 'V. Erspamer', University of Rome 'Sapienza' , Rome , Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Iacovelli
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Porcelli
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Maddalena
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.|b Lieber Institute for Brain Development, Johns Hopkins University Medical Campus , Baltimore , MD , US.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Punzi
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mancini
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Masellis
authors.affiliation: g Center of Neuropharmacology; Dipartimento di Scienze Farmacologiche e Biomolecolari; Università degli Studi di Milano , Milan , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.affiliation: h Department of Neuroradiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Italy.
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.affiliation: e Istituto di Endocrinologia e Oncologia Sperimentale, IEOS, CNR, and Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli 'Federico II' , Naples.
authors.forename: Simona
authors.initials: S
authors.lastname: Keller
authors.affiliation: c Department of Clinical and Community Sciences, Università degli Studi di Milano , Milan , Italy.|d Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Maggiore Hospital, Mangiagalli and Regina Elena Foundation , Milan , Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Tarantini
authors.affiliation: i Mendel Laboratory, Istituto di Ricoveroe Cura a Carattere Scientifico (IRCCS) 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sinibaldi
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.|j Cognitive Brain Research Unit, Institute of Behavioral Sciences, University of Helsinki , Helsinki , Finland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Quarto
authors.affiliation: h Department of Neuroradiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: g Center of Neuropharmacology; Dipartimento di Scienze Farmacologiche e Biomolecolari; Università degli Studi di Milano , Milan , Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: k Department of Molecular Medicine, University of Rome 'Sapienza' , Rome , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Blasi
authors.affiliation: e Istituto di Endocrinologia e Oncologia Sperimentale, IEOS, CNR, and Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli 'Federico II' , Naples.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Chiariotti
authors.affiliation: c Department of Clinical and Community Sciences, Università degli Studi di Milano , Milan , Italy.|d Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Maggiore Hospital, Mangiagalli and Regina Elena Foundation , Milan , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.affiliation: a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.|h Department of Neuroradiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D008570:Memory, Short-Term; D008715:Methionine; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D011485:Protein Binding; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D014633:Valine
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D008715:Methionine; D014633:Valine; C107989:BHLHE40 protein, human; C579455:BDNF protein, human
keywords: BDNF; DNA methylation; epigenetics; hypoxia; obstetric complications; prefrontal cortex; rs6265; schizophrenia; working memory