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

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.

Figure 1

Effect of the translocation on cortical thickness and local gyrification index. (a) Cortical thickness and (b) local gyrification difference between translocation carriers and non-carriers rendered on the inflated and non-inflated cortical surface of the left and right brain templates. Columns 1, 3, 5, and 7 show the significance map of the difference; columns 2, 4, 6, and 8 show the regions that survive the cluster-wise multiple comparisons correction (P<0.05). The blue color indicates that the cortex is thinner and less gyrified for the translocation carriers compared with non-carriers, whereas the red color indicates the opposite effect. All these analyses are controlled for age and sex. Note however that only left superior temporal sulcus cortical thickness and right superior frontal sulcus gyrification index are robust to controlling for intra-familial relatedness (see text). LGI, local gyrification index.

Figure 2

Effect of increasing working memory load on blood oxygen level-dependent activity measures in translocation carriers and non-carriers. Coronal sections through the brain to show the effects of increasing working memory load (from 0- to 1- to 2-back) in the N-back task on functional MRI in t(1;11) translocation carriers and non-carriers. The image is thresholded at P<0.001, uncorrected, to show regional activations. These were statistically significant in/across both groups in bilateral inferior, middle, and superior frontal cortices, bilateral inferior parietal lobules, right cerebellum, left inferior temporal gyrus, and the left middle orbital gyrus at P<0.05, family-wise error corrected for multiple comparisons. There were no statistically significant group differences at a family-wise error-corrected threshold of P<0.05.

Figure 3

Differential brain activation during increasing working memory load between translocation carriers and non-carriers. The effects of increasing working memory load (from 0- to 1- to 2-back) in the N-back task on functional MRI comparing t(1;11) translocation carriers and non-carriers, controlling for age and sex. (a) Transverse slice (z=22) displaying the statistically significant group×load interaction in left caudate, a family-wise error-corrected P<0.05. (b) Contrast estimates in the left caudate for 2-back>0-back for t(1;11) carriers and non-carriers to indicate the size of the effect.