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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.

Reference:
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: Can combining data from blood and brain microarray studies uncover biomarkers of schizophrenia? Are the putative biomarker candidates identified in a combined blood-brain data set any better than the ones identified in peripheral biomarker studies? According to the authors, their approach will “…facilitate the discovery of highly reliable and reproducible candidate risk genes and biomarkers for SZ.” Unfortunately, previous attempts in identifying such peripheral markers were mostly unsuccessful, yet high-throughput expression profiling methods may have a chance to identify the proverbial needle in the haystack. However, only future replications of these findings will resolve if the approach presented in this manuscript represents a breakthrough in the search for peripheral schizophrenia biomarkers.

The authors employ an intriguing and novel data-mining strategy using CORGON. Unfortunately, while this software has produced improved false discovery in non-neural data sets, we have little information on its...  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 increased SELENBP1 in schizophrenia is very interesting. Might that result in reduced function of the recently described anti-inflammatory gene selenoprotein S on chromosome 15 (1)? Curran et al. report that suppression of SEPS1 results in increased release of TNFα and Il-6. Gilmore et al. (2) report that cytokines generated in response to infection, IL-1β, TNFα, and IL-6 can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia.

References:
1. Curran JE, Jowett JB, Elliott KS, Gao Y, Gluschenko K, Wang J, Azim DM, Cai G, Mahaney MC, Comuzzie AG, Dyer TD, Walder KR, Zimmet P, Maccluer JW, Collier GR, Kissebah AH, Blangero J. Genetic variation in selenoprotein S influences inflammatory response. Nat Genet. 2005 Oct 9; [Epub ahead of print] Abstract

2. Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM. Prenatal Infection and Risk for Schizophrenia: IL-1beta, IL-6, and TNFalpha Inhibit Cortical Neuron Dendrite Development. Neuropsychopharmacology. 2004 Jul;29(7):1221-9. Abstract

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 that acetaminophen cytotoxicity is enhanced in selenium-binding protein-overexpressed COS-1 cells may help explain the results reported by the Mortensen group in two separate studies. In one, they find that mothers who take aspirin and acetaminophen during the second trimester have a fourfold risk of giving birth to a child who later develops schizophrenia as an adult (2). In the other, they report an increased risk of schizophrenia following paracetamol poisoning (3). It would seem that should SELENBP1 be a valid marker for the diagnosis of schizophrenia, then paracetamol would be contraindicated.

A further study by Ishida and colleagues (4) reports induction of hepatic selenium-binding protein by aryl hydrocarbon receptor ligands in rats. Does this suggest that AHR ligands such as polycyclic aromatic hydrocarbons and polychlorinated dioxin compounds may cause schizophrenia? Does this explain the reports of schizophrenia in the Vietnam veterans?

References:
1. Ishida T, Abe M, Oguri K, Yamada H. Enhancement of acetaminophen cytotoxicity in selenium-binding protein-overexpressed COS-1 cells. Drug Metab Pharmacokinet. 2004 Aug;19(4):290-6. Abstract

2. Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA. Association between prenatal exposure to analgesics and risk of schizophrenia. Br J Psychiatry. 2004 Nov;185:366-71. Abstract

3. Jepsen P, Qin P, Norgard B, Agerbo E, Mortensen PB, Vilstrup H, Sorensen HT. The association between admission for poisoning with paracetamol or other weak analgesics and subsequent admission for psychiatric disorder: a Danish nationwide case-control study. Aliment Pharmacol Ther. 2005 Oct 1;22(7):645-51. Abstract

4. Ishida, T., Ishii, Y., Yamada, H., and Oguri, K. The induction of hepatic selenium-binding protein by aryl hydrocarbon (Ah)-receptor ligands in rats. J. Health Sci., 48: 62-68, 2002.

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 2005
I wish we knew more of the function of SELENBP1, other than the fact that it binds selenium. Does it sequester it, thus making it unavailable for biological activity, or is it a transporter or receptor for selenium, making it more active/available? Unfortunately, the ontology of the gene is poorly documented. One distinct possibility is that the role of the gene/protein is better understood, but under a pseudonym, such as heat shock protein 56 (HSP56). We need to do more reading into this possibility to determine what the role of the protein is, but we do know that it is expressed in the growing tips of neurites.

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 2005
Replication will be key, and we hope that others will utilize gene expression microarrays to search for potential schizophrenia biomarkers as we have done. Our findings of dysregulation of specific myelin-related genes are consistent with prior work, as is the energy pathway dysfunction. Our work in conjunction with the others is painting a consistent picture of dysfunction in schizophrenia.

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 regarding the function of SELENBP1. Porat et al. find that 56SBP participates in late-stage intra-Golgi transport, but suggest that it may have more than one physiological role. The authors propose that SBP56 is active downstream of the Rab proteins. Might it be worthwhile to look at Rab36-22q11.2? A study by Mori et al. localized Rab36 at the Golgi body, suggesting that it is involved in vesicular transport around the Golgi apparatus.

References:
Porat A, Sagiv Y, Elazar Z. A 56-kDa selenium-binding protein participates in intra-Golgi protein transport. J Biol Chem. 2000 May 12;275(19):14457-65. Abstract

Mori T, Fukuda Y, Kuroda H, Matsumura T, Ota S, Sugimoto T, Nakamura Y, Inazawa J. Cloning and characterization of a novel Rab-family gene, Rab36, within the region at 22q11.2 that is homozygously deleted in malignant rhabdoid tumors. Biochem Biophys Res Commun. 1999 Jan 27;254(3):594-600. Abstract

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 expression differences in postmortem brain samples from individuals with schizophrenia and nonpsychiatric control samples. The researchers then compared these profiles with expression differences observed in blood from a separate sample of schizophrenic and nonpsychiatric controls.

Since there is no gold standard for the statistical evaluation of microarray data analysis, many alternative methods have been reported. In this study, Glatt et al. adopted their original method termed CORGON. One of the features of their method is treatment of noise. They assumed multiplicative rather than additive noise. Though it is difficult to evaluate the possible advantageous effect of assuming multiplicative rather than additive noise on the data set presented, analytical models which assume that the error of the observed expression signals of microarray is multiplicative have been well studied recently. Multiplicative models appear to be more suitable than simple additive models, at least for some microarray data sets. The...  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 agree that it is not obvious how such expression changes in opposite directions reflect a common biological mechanism. This is precisely why we focused our subsequent efforts on SELENBP1. It is also important to realize that perhaps many more genes had corresponding differential expression in the blood and brain, but we may not have detected them due to the highly conservative nature of our statistical analyses.

We would also underscore that we don't know what fold-change difference between groups is biologically meaningful, which is why we focus on the significance level instead. The change in SELENBP1 may not be large, but it seems to be highly reliable. Replication efforts should prove very helpful in establishing the utility of SELENBP1 to identify schizophrenia.

View all comments by Stephen J. Glatt

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