CNVs conferring risk of autism or schizophrenia affect cognition in controls

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Johan Thygesen, PhD student, Institute of Biological Psychiatry, Mental Health Centre Sct. Hans

“Certain rare copy-number variants in the genome have been linked to schizophrenia and autism, but despite of this their carriers do not always suffer from the diseases. In this paper that recently was published in Nature, the authors finds explanation for why some CNV carriers suffers from diseases, while others are disease-free”

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the expression of the disease. These CNVs are not fully penetrant, and may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike, and study their effects separate from that of disease manifest.

In this study a group of Icelandic CNV carriers were studied and showed that although disease-free, their brains are subtly different from those of controls that do not carry such mutations. The CNVs are very rare, and affect different cognitive functions. And many CNVs drive or accompany the development of diseases.

Results from the cognitive examination showed that CNV carriers have cognitive abilities between those of normal controls and patients with schizophrenia. A similar result was found in a search for structural variation in the brain affected by CNVs, structural magnetic resonance imaging (MRI) that was performed on a subset of the examined group. The results showed that duplication carriers show reciprocal changes in exactly the same regions altered in deletion carriers. This provides the first demonstration of allele-dose-dependent effects of CNVs on the structure of the human brain.

One of the missing pieces in our understanding of the pathogenesis of schizophrenia has been the nature of the physiologic function that is first perturbed in the disease or the perturbation of which leads to the disease. The study show that carriers who have not been diagnosed with autism, intellectual disability, or schizophrenia show intermediate phenotypes in brain structure that are in good agreement with the observations in first-episode psychosis. The study therefore lends support to the idea that the cognitive abnormalities are fundamental to schizophrenia as they are manifest in healthy carriers of CNVs conferring risk of the disease. This also raises the possibility that the difference between the patients and the healthy control carriers may be due to variation at the physiological level of the CNVs.

In overall the results show that cognitive abnormalities are not necessarily a consequence of the disease, rather that the risk of the disease may, be mediated through the cognitive abnormalities. Thereby CNVs may be used to identify individuals in whom schizophrenia-like cognitive abnormalities can be studied without the confounding effects of psychosis or medications. CNVs also provide the opportunity to search systematically for the biochemical foundations of the cognitive differences between the carrier and non-carrier controls. By studying these carriers more closely it may prove possible to pinpoint more precisely, which abnormalities put carriers at risk of developing schizophrenia.

The article “CNVs conferring risk of autism or schizophrenia affect cognition in controls” was published in Nature 505, 361–366 (16 January 2014).

Further information

Johan Thygesen, PhD Student, Institute of Biological Psychiatry at Mental Health Centre Sct. Hans