TY - JOUR
T1 - Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity
AU - Whalley, Heather C
AU - Dimitrova, Ralica
AU - Sprooten, Emma
AU - Dauvermann, MR
AU - Romaniuk , Liana
AU - Duff, Barbara
AU - Watson, Andrew
AU - Moorhead, Bill
AU - Bastin, Mark E.
AU - Semple, Scott
AU - Giles, Stephen
AU - Hall, Jeremy
AU - Thomson, Pippa
AU - Roberts, Neil
AU - Hughes, Zoe
AU - Brandon, Nick
AU - Dunlop, John
AU - Whitcher, Brandon
AU - Blackwood, Douglas
AU - McIntosh, Andrew M.
AU - Lawrie, Stephen M.
PY - 2015/6/23
Y1 - 2015/6/23
N2 - 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.
AB - 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.
KW - Bipolar Disorder/genetics
KW - Chromosomes, Human, Pair 1/genetics
KW - Chromosomes, Human, Pair 11/genetics
KW - Corpus Callosum/pathology
KW - Cyclothymic Disorder/genetics
KW - Depressive Disorder, Major/genetics
KW - Diffusion Tensor Imaging
KW - Exons/genetics
KW - Nerve Tissue Proteins/deficiency
KW - Schizophrenia/genetics
KW - Severity of Illness Index
KW - Translocation, Genetic
KW - White Matter/pathology
U2 - 10.1371/journal.pone.0130900
DO - 10.1371/journal.pone.0130900
M3 - Article
C2 - 26102360
SN - 1932-6203
VL - 10
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e0130900
ER -
