title: Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation.
abstract: Formal thought disorder is a major feature of schizophrenia and other psychotic disorders. It is heritable, found in healthy relatives of patients with schizophrenia and other mental disorders but knowledge of specific genetic factors is lacking. The aim of this study was to search for biologically relevant high-risk variants. Formal thought disorder was assessed in participants in the Copenhagen Schizophrenia Linkage Study (N=236), a unique high-risk family study comprised of six large pedigrees. Microsatellite linkage analysis of formal thought disorder was performed and subsequent haplotype analysis of the implicated region using phased microsatellite and SNP genotypes. Whole genome sequencing (N=3) was used in the attempt to identify causative variants in the linkage region. Linkage analysis of formal thought disorder resulted in a single peak at chromosome 6(q26-q27) centred on marker D6S1277, with a maximum LOD score of 4.0. Phasing and fine mapping of the linkage peak identified a 5.5Mb haplotype (chr6:162242322-167753547, hg18) in 31 individuals, all belonging to the same pedigree sharing the haplotype from a common ancestor. The haplotype segregated with increased total thought disorder index score (P=4.9 × 10(-5)) and qualitatively severe forms of thought disturbances. Whole genome sequencing identified a novel nucleotide deletion (chr6:164377205 AG>A, hg18) predicted to disrupt the potential binding of the transcription factor MEF2A. The MEF2A binding site is located between two genes previously reported to associate with schizophrenia, QKI (HGNC:21100) and PDE10A (HGNC:8772). The findings are consistent with MEF2A deregulation conferring risk of formal thought disorder.
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. Electronic address: johan.hilge.thygesen@regionh.dk.
authors.forename: Johan Hilge
authors.initials: JH
authors.lastname: Thygesen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. Electronic address: sinezambach@gmail.com.
authors.forename: Sine Katharina
authors.initials: SK
authors.lastname: Zambach
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; deCODE genetics/Amgen, Sturlugata 8, 101 Reykjavík, Iceland. Electronic address: andres.ingason@decode.is.
authors.forename: Andrés
authors.initials: A
authors.lastname: Ingason
authors.affiliation: deCODE genetics/Amgen, Sturlugata 8, 101 Reykjavík, Iceland. Electronic address: par.lundin@gmail.com.
authors.forename: Pär
authors.initials: P
authors.lastname: Lundin
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. Electronic address: thomas.hansen@regionh.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. Electronic address: marcelo.bertalan.q.dos.santos@regionh.dk.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Bertalan
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. Electronic address: anders.rosengren@regionh.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Rosengren
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark. Electronic address: dittebjerre@yahoo.dk.
authors.forename: Ditte
authors.initials: D
authors.lastname: Bjerre
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark. Electronic address: laura.ferrero@regionh.dk.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferrero-Miliani
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark. Electronic address: henrik.berg.rasmussen@regionh.dk.
authors.forename: Henrik Berg
authors.initials: HB
authors.lastname: Rasmussen
authors.affiliation: Psychiatric center Hvidovere, Brøndbyøstervej 160, 2605 Brøndby, Denmark; Center for Subjectivity Research, University of Copenhagen, Njalsgade 142, 2300 Copenhagen S, Denmark. Electronic address: jpa@hum.ku.dk.
authors.forename: Josef
authors.initials: J
authors.lastname: Parnas
authors.affiliation: Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Boserupvej 2, 4000 Roskilde, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark; Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Blegdamsvej 3, 2300 Copenhagen N, Denmark. Electronic address: thomas.werge@regionh.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002896:Chromosomes, Human, Pair 6; D003718:Denmark; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008137:Longitudinal Studies; D064326:MEF2 Transcription Factors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C490832:QKI protein, human; D016601:RNA-Binding Proteins; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Endophenotypes; High risk families; Linkage analysis; Schizophrenia; Thought disorder; Whole genome sequencing