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Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity

van Amelsvoort, Therese, Whalley, Heather C., Dimitrova, Rali, Sprooten, Emma, Dauvermann, Maria R., Romaniuk, Liana, Duff, Barbara, Watson, Andrew R., Moorhead, Bill, Bastin, Mark, Semple, Scott I., Giles, Stephen, Hall, Jeremy, Thomson, Pippa, Roberts, Neil, Hughes, Zoe A., Brandon, Nick J., Dunlop, John, Whitcher, Brandon, Blackwood, Douglas H. R., McIntosh, Andrew M. and Lawrie, Stephen M. 2015. Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity. PLoS ONE 10 (6) , e0130900. 10.1371/journal.pone.0130900

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Additional Information: © 2015 Whalley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 08:37
URI: http://orca.cf.ac.uk/id/eprint/81279

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Cited 1 time in Web of Science. View in Web of Science.

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