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Panos Roussos, MD, PhD; Pavel Katsel, PhD; Kenneth L. Davis, MD; Panos Bitsios, MD, PhD; Stella G. Giakoumaki, PhD; Jigar Jogia, PhD; Kinga Rozsnyai, MSc; David Collier, PhD; Sophia Frangou, MD, PhD; Larry J. Siever, MD; Vahram Haroutunian, PhD

Arch Gen Psychiatry. 2012;69(1):7-15. doi:10.1001/archgenpsychiatry.2011.110

Context  Genetic, neuroimaging, and molecular neurobiological evidence support the hypothesis that the disconnectivity syndrome in schizophrenia (SZ) could arise from failures of saltatory conduction and abnormalities at the nodes of Ranvier (NOR) interface where myelin and axons interact.

Objective  To identify abnormalities in the expression of oligodendroglial genes and proteins that participate in the formation, maintenance, and integrity of the NOR in SZ.

Design  The messenger RNA (mRNA) expression levels of multiple NOR genes were quantified in 2 independent postmortem brain cohorts of individuals with SZ, and generalizability to protein expression was confirmed. The effect of the ANK3 genotype on the mRNA expression level was tested in postmortem human brain. Case-control analysis tested the association of the ANK3 genotype with SZ. The ANK3 genotype's influence on cognitive task performance and functional magnetic resonance imaging activation was tested in 2 independent cohorts of healthy individuals.

Setting  Research hospital.

Patients  Postmortem samples from patients with SZ and healthy controls were used for the brain expression study (n = 46) and the case-control analysis (n = 272). Healthy white men and women participated in the cognitive (n = 513) and neuroimaging (n = 52) studies.

Main Outcome Measures  The mRNA and protein levels in postmortem brain samples, genetic association with schizophrenia, cognitive performance, and blood oxygenation level–dependent functional magnetic resonance imaging.

Results  The mRNA expression of multiple NOR genes was decreased in schizophrenia. The ANK3 rs9804190 C allele was associated with lower ANK3 mRNA expression levels, higher risk for SZ in the case-control cohort, and poorer working memory and executive function performance and increased prefrontal activation during a working memory task in healthy individuals.

Conclusions  These results point to abnormalities in the expression of genes and protein associated with the integrity of the NOR and suggest them as substrates for the disconnectivity syndrome in SZ. The association of ANK3 with lower brain mRNA expression levels implicates a molecular mechanism for its genetic, clinical, and cognitive associations with SZ.

Author Affiliations: Department of Psychiatry, The Mount Sinai School of Medicine, New York (Drs Roussos, Katsel, Davis, Siever, and Haroutunian), and James J. Peters Veterans Affairs Medical Center, Bronx (Drs Roussos, Siever, and Haroutunian), New York; Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece (Drs Roussos, Bitsios, and Giakoumaki); and Section of Neurobiology of Psychosis (Drs Jogia and Frangou) and Social, Genetic, and Developmental Psychiatry Research Centre (Ms Rozsnyai and Dr Collier), Institute of Psychiatry, King's College London, England.

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