Linkage and Whole Genome Sequencing Identify a Locus on 6q25–26 for Formal Thought Disorder and Implicate MEF2A Regulation

Johan Hilge Thyegesen, Sine Katharina Zambach, Andrés Ingason, Pär Lundin, Thomas Hansen, Marcelo Bertalan, Anders Rosengren, Ditte Bjerre, Laura Ferrero-Miliani, Henrik Berg Rasmussen, Josef Parnas, Thomas Werge

Research output: Contribution to journalJournal articleResearchpeer-review

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 5.5 Mb 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.
Original languageEnglish
JournalSchizophrenia Research
Volume169
Issue number1-3
Pages (from-to)441-446
Number of pages6
ISSN0920-9964
DOIs
Publication statusPublished - Dec 2015
Externally publishedYes

Keywords

  • Schizophrenia
  • Linkage analysis
  • Whole genome sequencing
  • Endophenotypes
  • High risk families
  • Thought disorder

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