Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation
| Autor: | Johan H. Thygesen, Josef Parnas, Marcelo Bertalan, Sine Zambach, Pär Lundin, Laura Ferrero-Miliani, Thomas Hansen, Ditte Bjerre, Anders Rosengren, Thomas Werge, Henrik B. Rasmussen, Andres Ingason |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Candidate gene Adolescent Genotype Genetic Linkage Denmark Locus (genetics) Pedigree chart Biology Statistics Nonparametric Young Adult Genetic linkage medicine Humans Genetic Predisposition to Disease Longitudinal Studies Biological Psychiatry Aged Genetics Whole genome sequencing Aged 80 and over Genome Human MEF2 Transcription Factors Phosphoric Diester Hydrolases Haplotype Thought disorder Genetic Variation RNA-Binding Proteins Sequence Analysis DNA Middle Aged Psychiatry and Mental health Schizophrenia Microsatellite Chromosomes Human Pair 6 Female medicine.symptom Lod Score |
| Zdroj: | Schizophrenia research. 169(1-3) |
| ISSN: | 1573-2509 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect