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. Genetics: Chromosomal rearrangement linked to brain changes A chromosome abnormality linked to psychiatric illness leads to changes in the brain that could explain its role. It has been more than 25 years since researchers first described how a rearrangement between chromosomes 1 and 11 was a major risk factor for schizophrenia, bipolar disorder and depression, but the exact effect of this abnormality on the brain has remained unclear. Now, a team led by Stephen Lawrie from the University of Edinburgh in the United Kingdom has conducted brain scans on members of an extended Scottish family. Family members who carried the chromosomal rearrangement—and thus had much higher rates of mental illness—had structural and functional alterations in their brains that included reduced cortical thickness, increased activation in the caudate nucleus and decreased glutamate levels when compared to non-carriers.