title: Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms.
abstract: Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age-12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems.
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Fisher
authors.affiliation: b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Therese M
authors.initials: TM
authors.lastname: Murphy
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Arseneault
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.|c Department of Psychology and Neuroscience ; Duke University ; Durham , NC , USA.|d Department of Psychiatry and Behavioral Sciences ; Duke University Medical School ; Durham , NC , USA.
authors.forename: Avshalom
authors.initials: A
authors.lastname: Caspi
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.|c Department of Psychology and Neuroscience ; Duke University ; Durham , NC , USA.|d Department of Psychiatry and Behavioral Sciences ; Duke University Medical School ; Durham , NC , USA.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Moffitt
authors.affiliation: b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Viana
authors.affiliation: b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: e Garvan Institute of Medical Research ; Darlinghurst , NSW , Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.affiliation: b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Burrage
authors.affiliation: b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Dempster
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.
authors.forename: Chloe C Y
authors.initials: CC
authors.lastname: Wong
authors.affiliation: f Department of Psychological Medicine ; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.
authors.forename: Carmine M
authors.initials: CM
authors.lastname: Pariante
authors.affiliation: a MRC Social , Genetic & Developmental Psychiatry Center; Institute of Psychiatry , Psychology & Neuroscience; King's College London ; London , UK.|b University of Exeter Medical School; University of Exeter ; Exeter , Devon , UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
mesh_terms: D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011618:Psychotic Disorders / Q000097:blood / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C572460:CPLANE1 protein, human; D008565:Membrane Proteins
keywords: DNA methylation; biomarker; epigenetics; longitudinal study; psychosis; schizophrenia; twins