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WCPG 2005: SELENBP1 Joins Array of Schizophrenia Gene Candidates

19 October 2005. A new DNA microarray study of schizophrenia patients in the U.S. and Taiwan suggests that the selenium-binding protein, SELENBP1, might be a viable candidate for a schizophrenia-associated gene. The finding, presented at the World Congress on Psychiatric Genetics in Boston on October 15, and reported as an advanced online publication in the Proceedings of the National Academy of Sciences online, also hints that SELENBP1 might serve as an easily detectible biomarker because in those with the disease, the amount of the protein in peripheral blood cells is higher than normal.

Since it became generally accepted that susceptibility to schizophrenia reflects subtle variation among multiple genes, scientists have tried every means at their disposal to identify genetic changes that increase the risk of developing the disease. Over the last 5 years or so, genetic linkage and association studies of families affected by the illness have identified several strong candidate genes, including, among others, dysbindin, neuregulin-1, and disrupted in schizophrenia (DISC1), (for a recent review, see Owen et al., 2005).

Microarray analysis adopts a slightly different approach. By simultaneously comparing the expression, or activity, of thousands of genes, it can identify which ones are expressed differently in patients versus normal individuals. The technique has already been used to make short lists of up- and down-regulated genes that may contribute to schizophrenia (see, for example, Prabakaran et al., 2004 and Iwamoto et al., 2005). However, microarray analysis is not without problems, most notorious being the number of false-positive findings.

In this new study, from the lab of Ming Tsuang and colleagues at the University of California at San Diego and collaborating institutes, first author Stephen Glatt and colleagues used various approaches to minimize the problems with and increase the validity of this approach. First and foremost, they have used a statistical software tool developed by two of the co-authors (and freely available) that reduces—by three- to fivefold—the number of false-positives returned by commonly used methods. In addition, they have corrected for the potential confounding influences of prescription medication—which could account for major differences in array profiles between patients and controls—and they have increased the robustness of the findings by carrying out the analysis on two different tissue samples (brain and blood) taken from two different populations (U.S. and Taiwan).

The authors profiled tissue samples taken postmortem from the dorsolateral prefrontal cortex (a region of the brain most associated with the illness) of 19 schizophrenia patients and 27 control subjects in the U.S. This analysis revealed 177 genes that were differentially expressed (111 up-regulated and the remainder down-regulated in the patients). Separate analysis of blood samples from 30 patient and 24 control volunteers from Taiwan, revealed 123 genes that were differentially expressed (67 up-regulated and 56 down-regulated in patients). Comparing these two data sets revealed six genes in common (BTG1, GSK3A, HLA-DRB1, HNRPA3, SELENBP1, and SFRS1). Five of these were either up-regulated in blood and down-regulated in brain, or vice versa, whereas SELENBP1 was up-regulated in both blood and brain tissue taken from those with the illness. The authors found that the effects of various medications—anticonvulsants, antidepressants, antipsychotics—on gene expression was not statistically significant.

How a selenium-binding protein may relate to schizophrenia is presently unclear, but because it was up-regulated in both tissues, the authors chose it for further analysis. They were able to validate their findings directly; amplification of SELENBP1 RNA confirmed that the gene is up-regulated in peripheral blood cells and antibodies to SELENBP1 detected more of the protein in DLPFC neurons and glia from those affected by the illness. The possible relationship between SELENBP1 and schizophrenia could center around the antioxidant role of selenium or previously established links between selenium deficiency and the sometimes toxic effects of the neurotransmitter glutamate, suggest the authors.—Tom Fagan.

Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Hkaniou MH, Liew C-C, Tsuang MT. Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. PNAS Early Edition. October 13, 2005. Abstract

Comments on News and Primary Papers
Primary Papers: Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia.

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 21 October 2005 Posted 21 October 2005

The manuscript by Glatt et al. raises important questions:...  Read more

View all comments by Karoly Mirnics

Comment by:  Mary Reid
Submitted 21 October 2005 Posted 21 October 2005

The study by Ming Tsuang and colleagues reporting...  Read more

View all comments by Mary Reid

Comment by:  Mary Reid
Submitted 21 October 2005 Posted 21 October 2005

I wonder whether the study by Ishida et al. (1) finding...  Read more

View all comments by Mary Reid

Comment by:  Stephen J. Glatt
Submitted 25 October 2005 Posted 25 October 2005
  I recommend the Primary Papers

Response to comment by Mary Reid posted 21 October...  Read more

View all comments by Stephen J. Glatt

Comment by:  Stephen J. Glatt
Submitted 25 October 2005 Posted 26 October 2005
  I recommend the Primary Papers

Response to comment by Karoly Mirnics posted 21 October...  Read more

View all comments by Stephen J. Glatt

Comment by:  Mary Reid
Submitted 26 October 2005 Posted 26 October 2005

It certainly will be of interest to see further studies...  Read more

View all comments by Mary Reid

Comment by:  Caroline GraffToru Kimura
Submitted 3 November 2005 Posted 3 November 2005

The paper by Glatt and coworkers reports on the gene...  Read more

View all comments by Caroline Graff
View all comments by Toru Kimura

Comment by:  Stephen J. Glatt
Submitted 7 November 2005 Posted 7 November 2005

Response to comment by Graff and Kimura
We...  Read more

View all comments by Stephen J. Glatt
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