The influence of copy number variation at the 22q11.2 locus on brain function

Abstract

Increased striatal dopamine synthesis capacity (DSC) and Glx (the combination of glutamate and glutamine) levels in anterior cingulate cortex (ACC), striatum and thalamus have been implicated in the pathophysiology of schizophrenia. However, there is only limited evidence in genetic high-risk groups. 22q11.2 deletion is the strongest genetic risk factor for schizophrenia, whereas the reciprocal duplication protects from the development of psychosis. Given the psychiatric phenotype of this mutation, many studies have previously examined its neuroanatomy. Moreover, the high variability of the phenotype suggests that different pathways may moderate the association between genes and phenotypic expression. To date, no study has investigated the structural variability in this mutation. In the first study, using [18]-FDOPA Positron Emission Tomography, I showed a significantly higher striatal DSC in the 22q11.2 deletion group compared to the groups of healthy controls and 22q11.2 duplication. Furthermore, DSC was positively correlated with the severity of sub-clinical positive psychotic symptoms. In the second study, using magnetic resonance spectroscopy, I found no difference in Glx levels in ACC, striatum and thalamus between 22q11.2 deletion carriers and controls. Moreover, there was no association between Glx levels and symptomatology. In my final study, I conducted an updated structural meta-analysis in individuals with 22q11.2 deletion. I demonstrated lower volume in total brain, grey and white matter, as well as in frontal, temporal lobe and hippocampus in 22q11.2 deletion compared to controls. Furthermore, 22q11.2 deletion carriers had higher hippocampal structural variability versus controls. Follow-up of my 22q11.2 deletion cohort is warranted to examine if the development of psychosis is associated with further dopaminergic dysfunction and if glutamatergic changes present at this stage of illness. Furthermore, using structural data from large scale studies, it would be interesting to investigate the potential utility of the increased variability of hippocampus as predictive biomarker for psychosis in 22q11.2DS.