title: Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity.
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).
  
  
  METHODS
  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.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Centre for the Developing Brain, St Thomas' Hospital, King's College London, London, United Kingdom.
authors.forename: Rali
authors.initials: R
authors.lastname: Dimitrova
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, United States of America.
authors.forename: Emma
authors.initials: E
authors.lastname: Sprooten
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; McGovern Institute for Brain Research, Cambridge, MA, United States of America.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Dauvermann
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Liana
authors.initials: L
authors.lastname: Romaniuk
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Duff
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Watson
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Bill
authors.initials: B
authors.lastname: Moorhead
authors.affiliation: Centre for Clinical Brain Sciences, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Bastin
authors.affiliation: Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, United Kingdom; British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Semple
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Giles
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hall
authors.affiliation: Department of Medical Genetics, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pippa
authors.initials: P
authors.lastname: Thomson
authors.affiliation: Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, United Kingdom; Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Roberts
authors.affiliation: Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, United States of America.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Hughes
authors.affiliation: Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, United States of America; Current affiliation: AstraZeneca Neuroscience IMED, Cambridge, MA, United States of America.
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, United States of America; Current affiliation: AstraZeneca Neuroscience IMED, Cambridge, MA, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: Clinical and Translational Imaging, Pfizer Inc, Cambridge, MA, United States of America.
authors.forename: Brandon
authors.initials: B
authors.lastname: Whitcher
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lawrie
mesh_terms: D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics* / Q000648:ultrastructure; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics* / Q000648:ultrastructure; D003337:Corpus Callosum / Q000473:pathology; D003527:Cyclothymic Disorder / Q000235:genetics* / Q000473:pathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology; D056324:Diffusion Tensor Imaging; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index; D014178:Translocation, Genetic; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins