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