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Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity

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Heather C Whalley, Ralica Dimitrova, Emma Sprooten, MR Dauvermann, Liana Romaniuk , Barbara Duff, Andrew Watson, Bill Moorhead, Mark E. Bastin, Scott Semple, Stephen Giles, Jeremy Hall, Pippa Thomson, Neil Roberts, Zoe Hughes, Nick Brandon, John Dunlop, Brandon Whitcher, Douglas Blackwood, Andrew M. McIntosh & 1 more Stephen M. Lawrie

Original languageEnglish
Article numbere0130900
JournalPLoS ONE
Volume10
Issue number6
DOIs
Accepted/In press25 May 2015
Published23 Jun 2015

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  • pone.0130900

    pone.0130900.pdf, 2 MB, application/pdf

    Uploaded date:16 Nov 2015

    Version:Final published version

    Licence:CC BY

King's Authors

Abstract

OBJECTIVE: Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3).

METHOD: Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33).

RESULTS: We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity.

CONCLUSIONS: We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis.

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