Genetic Variation and White Matter Deficits in Schizophrenia

Phillip R. Szeszko, Ph.D.

North Shore-Long Island Jewish Health System Foundation , Glen Oaks, NY

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

December 2006, for 3 years

Funding Amount:


Lay Summary

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.

Selected Publications

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.