Abstract
Objectives
Heat shock proteins (HSPs) are a promising candidate gene in schizophrenia as they are believed to play a protective role in the central nervous system. An alteration in the titers of antibodies to the HSPs in schizophrenia patients has been suggested. Association between the three polymorphisms of HSP70-1 (HSPA1A), HSP70-hom (HSPA1L) and HSP70-2 (HSPA1B) and schizophrenia has been reported. Therefore, this study investigated the association between an enlarged set of SNPs at HSP70 gene and schizophrenia.
Methods
Two hundred and ninety-four patients with schizophrenia and 287 controls were enrolled in the study. Genotypings of 5 SNPs of HSP70 were performed using pyrosequencing method. Haploview 3.2 was used to generate a linkage disequilibrium map and to test for Hardy–Weinberg equilibrium. Single locus and haplotype-based associations were tested. Tests for associations using and multi-marker haplotypes were performed by using a COCAPHASE v2.403. Association of SNP markers and clinical variables were analyzed by analysis of variance.
Results
Significant association was detected at rs2075799 (allele A, χ2 = 8.03, df = 1, P = 0.0046), but not at rs2227956 (P = 0.28), rs1043618 (P = 0.88), rs562047 (P = 0.47) or rs539689 (P = 0.32). In fact, the rs2075799*G/A genotype was more represented in patients with schizophrenia than in controls (χ2 = 8.23, df = 1, P = 0.0041). Haplotype based associations were also detected (global P value 0.000003); the T-A-C-C-G haplotype was more prevalent among the patients (odds ratio, OR 5.95). Sliding windows analysis revealed a major contribution from rs2227956 and rs2075799 (global-P value 0.0075), with T-A haplotype significantly associated with schizophrenia. There was no evidence of an association between the clinical variables and schizophrenia across the genotypes.
Conclusion
Our results raise the possibility that HSP70 gene (i.e., haplotypes of rs2075799) might be implicated in the development of schizophrenia, although limited by rare haplotypic association with the disease. Hence further studies from different ethnics should be performed to confirm these results.
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References
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th edn. Washington
Andreasen N, Nasrallah HA, Dunn V, Olson SC, Grove WM, Ehrhardt JC, Coffman JA, Crossett JH (1986) Structural abnormalities in the frontal system in schizophrenia. A magnetic resonance imaging study. Arch Gen Psychiatry 43:136–144
Bates PR, Hawkins A, Mahadik SP, McGrath JJ (1996) Heat stress lipids and schizophrenia. Prostaglandins Leukot Essent Fatty Acids 55:101–107
Boin F, Zanardini R, Pioli R, Altamura CA, Maes M, Gennarelli M (2001) Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry 6:79–82
Cavalli Sforza L (1994) The history and geography of human genes. Princeton University Press, Princeton
Fourie AM, Peterson PA, Yang Y (2001) Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2. Cell Stress Chaperones 6:282–295
Garcia-Osta A, Frechilla D, Del Rio J (2003) Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone. Prog Neuropsychopharmacol Biol Psychiatry 27:31–36
Goate AM, Cooper DN, Hall C, Leung TK, Solomon E, Lim L (1987) Localization of a human heat-shock HSP 70 gene sequence to chromosome 6 and detection of two other loci by somatic-cell hybrid and restriction fragment length polymorphism analysis. Hum Genet 75:123–128
Hanninen K, Katila H, Saarela M, Rontu R, Mattila KM, Fan M, Hurme M, Lehtimaki T (2007) Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci (in press)
Huttunen MO, Machon RA, Mednick SA (1994) Prenatal factors in the pathogenesis of schizophrenia. Br J Psychiatry Suppl 15–19
Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS, Han H, Serretti A (2003) TNFB polymorphism may be associated with schizophrenia in the Korean population. Schizophr Res 61:39–45
Kim JJ, Lee SJ, Toh KY, Lee CU, Lee C, Paik IH (2001) Identification of antibodies to heat shock proteins 90 and 70 kDa in patients with schizophrenia. Schizophr Res 52:127–135
Knight JG (1984) Is schizophrenia an autoimmune disease? A review. Methods Find Exp Clin Pharmacol 6:395–403
Knight JG, Menkes DB, Highton J, Adams DD (2007) Rationale for a trial of immunosuppressive therapy in acute schizophrenia. Mol Psychiatry
Lewis SW, Murray RM (1987) Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia. J Psychiatr Res 21:413–421
Lindquist S (1992) Heat-shock proteins and stress tolerance in microorganisms. Curr Opin Genet Dev 2:748–755
Milner CM, Campbell RD (1990) Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32:242–251
Milner CM, Campbell RD (1992) Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics 36:357–362
Nagao RT, Kimpel JA, Key JL (1990) Molecular and cellular biology of the heat-shock response. Adv Genet 28:235–274
Pae CU, Kim TS, Kwon OJ, Artioli P, Serretti A, Lee CU, Lee SJ, Lee C, Paik IH, Kim JJ (2005) Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia. Neurosci Res 53:8–13
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Sargent CA, Dunham I, Trowsdale J, Campbell RD (1989) Human major histocompatibility complex contains genes for the major heat shock protein HSP70. Proc Natl Acad Sci USA 86:1968–1972
Schwab SG, Hallmayer J, Freimann J, Lerer B, Albus M, Borrmann-Hassenbach M, Segman RH, Trixler M, Rietschel M, Maier W, Wildenauer DB (2002) Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia. Am J Med Genet 114:315–320
Schwarz MJ, Riedel M, Gruber R, Ackenheil M, Muller N (1999) Antibodies to heat shock proteins in schizophrenic patients: implications for the mechanism of the disease. Am J Psychiatry 156:1103–1104
Suto R, Srivastava PK (1995) A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269:1585–1588
Walsh D, Li K, Crowther C, Marsh D, Edwards M (1991) Thermotolerance and heat shock response during early development of the mammalian embryo. Results Probl Cell Differ 17:58–70
Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669
Welch WJ (1991) The role of heat-shock proteins as molecular chaperones. Curr Opin Cell Biol 3:1033–1038
Wolgemuth DJ, Gruppi CM (1991) Heat shock gene expression during mammalian gametogenesis and early embryogenesis. Results Probl Cell Differ 17:138–152
Wright P, Nimgaonkar VL, Donaldson PT, Murray RM (2001) Schizophrenia and HLA: a review. Schizophr Res 47:1–12
Acknowledgements
This study was supported by a Grant (KRF-2004-003-E00145) from Korea Research Foundation. The authors would like to express a sincere gratitude to all the patients participated in the study.
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Kim, J.J., Mandelli, L., Lim, S. et al. Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia. Eur Arch Psychiatry Clin Neurosc 258, 239–244 (2008). https://doi.org/10.1007/s00406-007-0791-6
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DOI: https://doi.org/10.1007/s00406-007-0791-6