Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function.
Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels.
Medical Genetics Section, Centre for Genomic and Experimental Medicine, University of Edinburgh, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital , Edinburgh, UK.
Pippa A
PA
Thomson
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Barbara
B
Duff
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Douglas H R
DH
Blackwood
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Liana
L
Romaniuk
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Andrew
A
Watson
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Heather C
HC
Whalley
Clinical Research Imaging Centre (CRIC), The Queen's Medical Research Institute, University of Edinburgh , UK.
Xiang
X
Li
McGovern Institute for Brain Research, Massachusetts Institute of Technology , Cambridge, MA, USA.
Maria R
MR
Dauvermann
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
T William J
TW
Moorhead
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Catherine
C
Bois
Medical Genetics Section, Centre for Genomic and Experimental Medicine, University of Edinburgh, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital , Edinburgh, UK.
Niamh M
NM
Ryan
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Holly
H
Redpath
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Lynsey
L
Hall
Medical Genetics Section, Centre for Genomic and Experimental Medicine, University of Edinburgh, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital , Edinburgh, UK.
Stewart W
SW
Morris
Clinical Research Imaging Centre (CRIC), The Queen's Medical Research Institute, University of Edinburgh , UK.
Edwin J R
EJ
van Beek
Clinical Research Imaging Centre (CRIC), The Queen's Medical Research Institute, University of Edinburgh , UK.
Neil
N
Roberts
Medical Genetics Section, Centre for Genomic and Experimental Medicine, University of Edinburgh, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital , Edinburgh, UK.
David J
DJ
Porteous
Institute of Medical Sciences, University of Aberdeen , Aberdeen, UK.
David
D
St Clair
Clinical & Translational Imaging Group, Pfizer Global Research , Cambridge, MA, USA.
Brandon
B
Whitcher
Neuroscience Research Unit, Pfizer Global Research, Cambridge, MA, USA; AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, MA, USA.
John
J
Dunlop
Neuroscience Research Unit, Pfizer Global Research, Cambridge, MA, USA; AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, MA, USA.
Nicholas J
NJ
Brandon
Neuroscience Research Unit, Pfizer Global Research , Cambridge, MA, USA.
Zoë A
ZA
Hughes
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building , Cardiff, UK.
Jeremy
J
Hall
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Andrew
A
McIntosh
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
Stephen M
SM
Lawrie