Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation. / Thygesen, Johan Hilge; Zambach, Sine Katharina; Ingason, Andrés; Lundin, Pär; Hansen, Thomas; Bertalan, Marcelo; Rosengren, Anders; Bjerre, Ditte; Ferrero-Miliani, Laura; Rasmussen, Henrik Berg; Parnas, Josef; Werge, Thomas.
In: Schizophrenia Research, Vol. 169, No. 1-3, 12.2015, p. 441-6.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation
AU - Thygesen, Johan Hilge
AU - Zambach, Sine Katharina
AU - Ingason, Andrés
AU - Lundin, Pär
AU - Hansen, Thomas
AU - Bertalan, Marcelo
AU - Rosengren, Anders
AU - Bjerre, Ditte
AU - Ferrero-Miliani, Laura
AU - Rasmussen, Henrik Berg
AU - Parnas, Josef
AU - Werge, Thomas
N1 - Copyright © 2015 Elsevier B.V. All rights reserved.
PY - 2015/12
Y1 - 2015/12
N2 - 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.
AB - 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.
U2 - 10.1016/j.schres.2015.08.037
DO - 10.1016/j.schres.2015.08.037
M3 - Journal article
C2 - 26421691
VL - 169
SP - 441
EP - 446
JO - Schizophrenia Research
JF - Schizophrenia Research
SN - 0920-9964
IS - 1-3
ER -
ID: 160867393