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NPJ Schizophr. 2016 Aug 10;2:16024. doi: 10.1038/npjschz.2016.24. eCollection 2016.

Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function.

Author information

1
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.
2
Division of Psychiatry, Deanery of Clinical Sciences, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park , Edinburgh, UK.
3
Clinical Research Imaging Centre (CRIC), The Queen's Medical Research Institute, University of Edinburgh , UK.
4
McGovern Institute for Brain Research, Massachusetts Institute of Technology , Cambridge, MA, USA.
5
Institute of Medical Sciences, University of Aberdeen , Aberdeen, UK.
6
Clinical & Translational Imaging Group, Pfizer Global Research , Cambridge, MA, USA.
7
Neuroscience Research Unit, Pfizer Global Research, Cambridge, MA, USA; AstraZeneca Neuroscience, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, MA, USA.
8
Neuroscience Research Unit, Pfizer Global Research , Cambridge, MA, USA.
9
Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building , Cardiff, UK.

Abstract

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.

Conflict of interest statement

S.M.L. has received financial support for research from Roche and Abbvie in relation to therapeutic studies of people with schizophrenia. He has also received personal payment for input into educational initiatives from Roche, Janssen, and Sunovion. These received funds do not present a conflict of interest with the present study. B.W., J.D., N.J.B., and Z.A.H. are all current or former employees of Pfizer. J.D. and N.J.B. are current employees of AstraZeneca. The remaining authors declare no conflict of interest.

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