Genetic Variation and White Matter Deficits in Schizophrenia

Phillip R. Szeszko, Ph.D.

North Shore-Long Island Jewish Health System Foundation

Funded in December, 2006: $100000 for 3 years
LAY SUMMARY . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Genetic Variation and White Matter Deficits in Schizophrenia

This study will use diffusion tensor imaging (DTI) of the brain’s white matter (the neural communication cables) in people with schizophrenia and healthy volunteers, along with genetic mapping, to test the hypothesis that variation within specific genes influences white matter structure in this disease.

Recent genetics data suggests that people with schizophrenia have alterations in the brain’s white matter, which is composed of networks of nerve cell axons used to transmit communication signals. Scientists now have the potential to quantify axonal structure using newly developed DTI  technology.  DTI indirectly maps axonal structures by measuring where water in the brain has been displaced by axons. Concurrently, recent advances in genetic mapping have identified several candidate genes whose variations might be responsible for abnormal axonal connectivity in schizophrenia.

The researchers will map five genes thought to be involved in schizophrenia and test the hypothesis that variation within these genes influences white matter integrity, as assessed by DTI.  They will obtain genetic information from DNA contained in blood samples, and DTI-identified white matter differences, in 80 patients with schizophrenia compared to 80 healthy volunteers. If these combined techniques demonstrate statistically significant associations of genetic variations and white matter abnormalities in patients compared to healthy volunteers, the research could lead to identification of the gene products responsible and ways in which they might interact to give rise to schizophrenia.

Significance:  Statistically significant findings of associations between genetic variations and abnormal axonal connectivity in schizophrenia could lead to the development of novel compounds that target proteins encoded by the implicated genes.

HYPOTHESIS

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Hypothesis
Variation within genes linked to oligodendrocyte or myelin function will be associated with lower white matter integrity, as inferred by diffusion tensor imaging, in patients with schizophrenia and healthy volunteers.

Goals:
An abnormality in brain white matter connectivity has been one of the major hypotheses regarding the pathophysiology of schizophrenia.  New developments in neuroimaging and genetics now provide the methodology to directly test hypotheses that genetic variation within putative white matter genes is associated with white matter integrity.  Diffusion tensor imaging (DTI) is an in-vivo magnetic resonance (MR) imaging technique that is particularly suited for the investigation of white matter in humans. In addition to advances in neuroimaging, the recent completion of the human HapMap project now provides comprehensive genomic information on variability within the genome including candidate genes for white matter integrity. Coupled with improved genotyping technology, including the ability to efficiently develop customized genotyping arrays, these data now provide the first opportunity to densely map genes thought to be associated with white matter integrity.

Methods:
We will be assessing the relationship between genotype status and fractional anisotropy in patients with schizophrenia and healthy volunteers.  The primary genotyping approach will be the development of a customized Illumina Oligo Pool Array across the candidate white matter genes.  Phased haplotypes will be estimated for each subject incorporating Bayesian methods.  Subjects will also receive diffusion tensor imaging exams.  The primary form of analysis will be a voxelwise ANOVA performed on the DTI data incorporating haplotype, group and haplotype-by-group interaction in the statistical model.

SELECTED PUBLICATIONS

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Kumra S., Ashtari M., Cervellione K.L., Henderson I., Kester H., Roofeh D., Wu J., Clarke T., Thaden E., Kane J.M., Fisch G., Rhinewine J., Lencz T., Diamond A., Ardekani B.A., and Szeszko P.R.  White matter abnormalities in early-onset schizophrenia: a voxel based diffusion tensor imaging study. J Am Acad Child Adolesc Psychiatry. 2005 Sep;44(9):934-41.

Szeszko P.R., Lipsky R., Mentschel C., Robinson D., Gunduz-Bruce H., Sevy S., Ashtari M., Napolitano B., Bilder R.M., Kane J.M., Goldman D., and Malhotra A.K. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005 Jul;10(7):631-6.

Szeszko P.R., Ardekani B.A., Ashtari M., Malhotra A.K., Robinson D.G., Bilder R.M., and Lim K.O.  White matter abnormalities in obsessive-compulsive disorder: a diffusion tensor imaging study.  Arch Gen Psychiatry. 2005 Jul;62(7):782-90.

Szeszko P.R., Ardekani B.A., Ashtari M., Kumra S., Robinson D.G., Sevy S., Gunduz-Bruce H., Malhotra A.K., Kane J.M., Bilder R.M., and Lim K.O. White matter abnormalities in first-episode schizophrenia or schizoaffective disorder: a diffusion tensor imaging study. Am J Psychiatry. 2005 Mar;162(3):602-5.