Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene - PubMed (original) (raw)

doi: 10.1086/507566. Epub 2006 Jul 31.

Jurg Ott, Sandra Barral, Pierre Bovet, Patricia Deppen, Fulvia Gheorghita, Marie-Louise Matthey, Josef Parnas, Martin Preisig, Michael Saraga, Alessandra Solida, Sally Timm, August G Wang, Thomas Werge, Michel Cuénod, Kim Quang Do

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Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene

Mirjana Tosic et al. Am J Hum Genet. 2006 Sep.

Abstract

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.

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Figures

Figure  1.

Figure 1.

GSH metabolic pathway. The genes for which expression was studied in fibroblast cultures from skin biopsies are highlighted. Black indicates no difference between controls and patients, and red indicates lower expression in patients compared with controls. These genes code for the enzymes highlighted in yellow. Substrates and products are highlighted in purple. Genes not directly involved in GSH metabolism but included in the expression study: Nrf1, Nrf2, and Nrf3 = NF-E2–related transcription factors 1, 2, and 3, respectively; xCT and 4F2 = genes encoding proteins involved in cystine/glutamate exchange; and MRP1 = multidrug resistance protein 1. ADP = adenosine diphospate; GSSG = glutathione disulfide; RSH = reduced thiols; RS = disulfide; N-AC-CYS-X = N-acetyl-cysteine conjugate; Pi = inorganic phosphate.

Figure  2.

Figure 2.

Map of GCLM and GSS genomic structures, with the positions of SNP markers and results of two case-control studies. Tables show P values for each SNP in case-control studies of subjects from two independent populations, from Switzerland and Denmark. Values in italics indicate a significant difference, and the value in bold italics indicates a significant difference after correction for multiple testing.

Figure  3.

Figure 3.

Genotype distribution of the two most common SNPs at the GCLM gene in the controls and patients sampled from a Danish population. The graph shows a dominance of the G allele for both markers.

Figure  4.

Figure 4.

GOLD plot of pairwise LD for 17 SNPs that belong to genes GCLM and GSS. The 17 SNPs used in association and linkage studies and graphically presented in figure 2 are labeled on both axes. The color differences represent regions of the local map that are in disequilibrium and the magnitude of that disequilibrium. Regions of high and low LD are presented in red and blue, respectively. GOLD plot shows very strong LD within each gene.

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References

Web Resources

    1. dbSNP, http://www.ncbi.nlm.nih.gov/SNP/
    1. International Classification of Diseases (ICD-10), http://www3.who.int/icd/currentversion/fr-icd.htm
    1. Online Mendelian Inheritance in Man (OMIM) http://www.ncbi.nlm.nih.gov/Omim/ (for schizophrenia)
    1. SNP Consortium, http://snp.cshl.org/

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