Linkage and whole genome sequencing identify a locus on 6q25-26 for formal thought disorder and implicate MEF2A regulation

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• 作者：Johan Hilge Thygesen^a ; ^b ; ^{johan.hilge.thygesen@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; ^{j.thygesen@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Sine Katharina Zambach^a ; ^b ; ^{sinezambach@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; André ; s Ingason^a ; ^c ; ^{andres.ingason@decode.is" class="auth_mail" title="E-mail the corresponding author} ; Pä ; r Lundin^c ; ^{par.lundin@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Thomas Hansen^a ; ^b ; ^{thomas.hansen@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Marcelo Bertalan^a ; ^b ; ^{marcelo.bertalan.q.dos.santos@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Anders Rosengren^a ; ^b ; ^{anders.rosengren@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Ditte Bjerre^a ; ^{dittebjerre@yahoo.dk" class="auth_mail" title="E-mail the corresponding author} ; Laura Ferrero-Miliani^a ; ^{laura.ferrero@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Henrik Berg Rasmussen^a ; ^{henrik.berg.rasmussen@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Josef Parnas^d ; ^e ; ^{jpa@hum.ku.dk" class="auth_mail" title="E-mail the corresponding author} ; Thomas Werge^a ; ^b ; ^f ; ^{thomas.werge@regionh.dk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CSLS ; Copenhagen schizophrenia linkage study ; FTD ; Formal thought disorder ; IGV ; Integrative genomics viewer ; LOD ; Logarithm of odds ; MAF ; Minor allele frequency ; sTRAP ; The SNP transcription factor affinity prediction ; TDI ; Thought disorder index ; WGS ; whole-genome sequencing
• 刊名：Schizophrenia Research
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：169
• 期：1-3
• 页码：441-446
• 全文大小：278 K

文摘

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.