Summary: Researchers have confirmed a connection between a specific genetic mutation and several major psychiatric disorders.
Source: University of Edinburgh.
Brain imaging reveals how a genetic translocation affecting the DISC1 gene alters brain structure, chemistry and function, and raises risk for schizophrenia, bipolar disorder and major depression.
New brain imaging evidence clarifies how a balanced chromosomal translocation that disrupts the DISC1 gene changes cortical anatomy, brain activity and neurotransmitter levels. These alterations help explain why carriers of the mutation face a substantially increased risk of major psychiatric illness.
Scientists leading the study at the University of Edinburgh used multiple brain imaging techniques to compare people who carry a specific balanced translocation—where part of one chromosome swaps places with part of another—with non-carrier relatives. The translocation interrupts the DISC1 gene, a gene long associated with schizophrenia, bipolar disorder and recurrent major depression.
The researchers report several consistent effects in translocation carriers. First, cortical thickness was reduced in the left temporal lobe, and this reduction correlated with overall psychiatric symptom severity and with the intensity of positive psychotic symptoms. Second, gyrification—how the cortex folds—was reduced in prefrontal regions, and this change also correlated with general psychopathology.
Functional imaging revealed that carriers showed abnormally increased activation in the caudate nucleus when verbal working memory demands rose. In parallel, magnetic resonance spectroscopy demonstrated lowered glutamate concentrations in the right dorsolateral prefrontal cortex of carriers. Reduced cortical glutamate has been implicated in schizophrenia in prior studies, and here it links directly to the DISC1 translocation.
Together, these structural, functional and chemical differences form a coherent picture: the t(1;11) balanced translocation that disrupts DISC1 is associated with altered brain architecture and neurochemistry that likely create a general vulnerability to a range of major psychiatric disorders. The study’s results strengthen the causal connection between this rare genetic variant and clinical diagnoses including schizophrenia, schizoaffective disorder, bipolar disorder and recurrent major depressive disorder.
The DISC1 translocation was first identified in a single Scottish family that showed unusually high rates of serious mental illness. Generations of that family have been studied for decades; this project reports the first detailed brain scans of affected family members and unaffected carriers, adding direct neurobiological evidence to previous genetic and clinical observations.
Lead authors and collaborators emphasize that studying rare, high-impact variants such as this one can reveal biological mechanisms that are hard to detect in broader population studies. By linking a specific genetic event to measurable changes in brain structure, activity and neurotransmitters, the findings point to pathways that could become targets for future treatment development.
Source: Jen Middleton, University of Edinburgh
Image source: Public domain illustrative image
Original research: Study titled “Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function” published in the journal Schizophrenia. Authors include Pippa A. Thomson, Barbara Duff, Douglas H. R. Blackwood, Liana Romaniuk, Andrew Watson, Heather C. Whalley, Xiang Li and colleagues; Stephen M. Lawrie is among the senior authors. Published online August 10, 2016.
Rare genetic variants with large biological effects can illuminate the pathophysiology of brain disorders. In this family-based study of a t(1;11)(q42;q14.3) balanced translocation, the translocation showed strong linkage to a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder and recurrent major depression. Carriers exhibited reduced cortical thickness in the left temporal lobe, reduced prefrontal gyrification, increased caudate activation during higher verbal working memory load, and decreased dorsolateral prefrontal glutamate concentrations. Cortical thickness and gyrification measures correlated with general psychopathology and positive psychotic symptoms. These convergent findings support the conclusion that the DISC1-disrupting translocation confers significantly increased risk for major psychiatric disorder by altering cortical structure, function and glutamatergic chemistry.
Understanding the chain of effects—from a single genetic rearrangement to measurable changes in brain anatomy and chemistry—offers a pathway for future work aimed at developing targeted interventions and improving diagnosis and treatment for people with genetic risk for serious mental illness.