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

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Johan Thygesen, PhD in Psychiatry, Psychiatric genetics research associate at University College London, Division of Psychiatry

The first author

Johan Hilge Thygesen has a PhD in Psychiatry from the Institute for Biological Psychiatry, Sct. Hans Roskilde and is currently working as research associate at University College London, Division of psychiatry.

About the study

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 are lacking. In this study our aim was to identify biologically relevant high-risk variants, predisposing for sever types of thought disorder.

Our study builds on the Copenhagen Schizophrenia Linkage Study, which is a unique high-risk family study comprised of six large Danish pedigrees, with detailed phenotypic description and genetic information available for more than 250 individuals. To identify high risk variants we performed microsatellite linkage analysis of formal thought disorder. By maximising the parameters to a fairly high level of thought disorder symptoms, we identified a linkage signal with a LOD score of 4. We subsequently identified the microsatellite haplotype giving rise to the signal and fine-mapped the region using phased microsatellite and SNP genotypes. The implicated haplotype was found to segregate between 31 individuals 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.

The linkage analysis was followed up with whole genome sequencing of three affected carriers, to search for potential causative variant(s). We focused the whole genome sequencing analysis on variants within the identified haplotype and on variants that where either unknown or rare with MAF < 0.01 in population samples. The latter was done, as we expect a causative variant to have medium to high effect otherwise it would be undetectable by linkage, thus we expect the variants to be rare, or else thought disorder would be more prevalent in the population (as a result of common high-risk variants). After filtering the variants based on our inclusion criteria we searched for variants with that would disrupt gene functioning or impair regulation. This identified no gene disruptive mutations, but a novel nucleotide deletion (chr6:164377205 AG > A, hg18) predicted to disrupt the potential binding of the transcription factor MEF2A, a key transcription factor involved in postsynaptic differentiation. The MEF2A binding site is located between two genes previously reported to associate with schizophrenia, QKI and PDE10A. While the predicted disruption of MEF2A binding by the nucleotide deletion awaits verification from functional studies, the findings are consistent with MEF2A deregulation conferring risk of formal thought disorder.

The identified variant is novel and is not found in the 1000 genomes data or in 2230 whole genome sequenced Icelandic samples at deCODE. Likewise the affected haplotype has not been found in 1000 in house Danish samples genotyped on the same SNP-array platform. We are still to search for it in the full iPSYCH sample, to determine if it can be identified outside of the affected pedigree.

This is to our knowledge the first study on formal thought disorder, a key psychopathological trait of schizophrenia and other psychotic conditions, which combines linkage analysis and next generation sequencing in an experimental strategy that has proven successful for several Mendelian diseases. The findings of this study lend support to the growing evidence that impaired MEF2A activity may be involved in the etiology of neuropsychiatric disorders, and that genetic variation in the region 6q26-27 is of specific importance for thought disorders and schizophrenia.

The article Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation, was published in Schizophrenia Research, 2015 Oct 1. [Epub ahead of print].

Facts about the study

  • 6q25-26 is shown to be a risk locus for formal thought disorder a key symptom of schizophrenia.
  • Whole genome sequencing identified a specific nucleotide deletion predicted to disrupt MEF2A regulation (a key transcription factor involved in postsynaptic differentiation) as a plausible mechanism behind the risk of increased symptoms of thought disorder.
  • The study show that linkage analysis of family based samples can be used to guide discovery in next generation sequencing for the identification of high-risk disease variants.
  • The analysis of sub clinical phenotypes, such as symptoms of thought disorder, can increase the power to detect genetic risk variants for psychiatric illnesses. 

Further information

Johan Hilge Thygesen, PhD in Psychiatry, Psychiatric genetics research Associate at University College London, Division of Psychiatry. Email: j.thygesen@ucl.ac.uk 

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