Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

Molecular Psychiatry volume 13, pages 930–938 (2008)Cite this article

Abstract

Colony stimulating factor 2 receptor, beta (CSF2RB) is the shared subunit of receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2) and IL5, and is responsible for the initiation of signal transduction triggered by ligand binding. In our previous study, we showed the evidence that the IL3 gene is associated with schizophrenia and the associations observed are sex-specific and dependent on family history (FH). In this article, we studied 10 single-nucleotide polymorphisms in the CSF2RB gene in the Irish Study of High-Density Schizophrenia Families (ISHDSF) and the Irish Case – Control Study of Schizophrenia (ICCSS), and tested allele and haplotype associations with schizophrenia. Using the pedigree disequilibrium test, we found that two markers (rs11705394 and rs7285064) reached nominal significance. In sex-stratified analyses, for both the markers the association signals were mainly derived from male subjects. In the ICCSS sample, we found that several markers (rs2072707, rs2284031 and rs909486) showed sex-specific and FH-dependent associations with schizophrenia. In multimarker haplotype analyses, both ISHDSF and ICCSS samples showed globally significant associations in multiple linkage disequilibrium (LD) blocks sharing minimal LD. Since CSF2RB is essential for IL3 signaling, the findings that both IL3 and CSF2RB showed sex-specific and FH-dependent associations suggest that the IL3 pathway is involved in schizophrenia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  Google Scholar 

  2. Chen X, Wang X, Hossain S, O’Neill FA, Walsh D, Pless L et al. Haplotypes spanning SPEC2, PDZ-G EF2 and ACSL6 genes are associated with schizophrenia. Hum Mol Genet 2006; 15: 3329–3342.

    Article  CAS  Google Scholar 

  3. Chen X, Wang X, Hossain S, O’Neill AF, Walsh D, van den Oord EJ et al. Interleukin 3 and schizophrenia: the impact of sex and family history. Mol Psychiatry 2007; 12: 273–282.

    Article  CAS  Google Scholar 

  4. Gaughran F . Immunity and schizophrenia: autoimmunity, cytokines, and immune responses. Int Rev Neurobiol 2002; 52: 275–302.

    Article  CAS  Google Scholar 

  5. Jones AL, Mowry BJ, Pender MP, Greer JM . Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol 2005; 83: 9–17.

    Article  CAS  Google Scholar 

  6. Kipnis J, Cardon M, Strous RD, Schwartz M . Loss of autoimmune T cells correlates with brain diseases: possible implications for schizophrenia? Trends Mol Med 2006; 12: 107–112.

    Article  CAS  Google Scholar 

  7. Bessler H, Levental Z, Karp L, Modai I, Djaldetti M, Weizman A . Cytokine production in drug-free and neuroleptic-treated schizophrenic patients. Biol Psychiatry 1995; 38: 297–302.

    Article  CAS  Google Scholar 

  8. Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Colombo F, Zagliani A et al. Cytokine profiles in drug-naive schizophrenic patients. Schizophr Res 2001; 47: 293–298.

    Article  CAS  Google Scholar 

  9. Rapaport MH, Delrahim KK . An abbreviated review of immune abnormalities in schizophrenia. CNS Spectr 2001; 6: 392–397.

    Article  CAS  Google Scholar 

  10. Chiavetto LB, Boin F, Zanardini R, Popoli M, Michelato A, Bignotti S et al. Association between promoter polymorphic haplotypes of interleukin-10 gene and schizophrenia. Biol Psychiatry 2002; 51: 480–484.

    Article  CAS  Google Scholar 

  11. He G, Zhang J, Li XW, Chen WY, Pan YX, Yang FP et al. Interleukin-10-1082 promoter polymorphism is associated with schizophrenia in a Han Chinese sib-pair study. Neurosci Lett 2006; 394: 1–4.

    Article  CAS  Google Scholar 

  12. Zanardini R, Bocchio-Chiavetto L, Scassellati C, Bonvicini C, Tura GB, Rossi G et al. Association between IL-1beta -511C/T and IL-1RA (86 bp)n repeats polymorphisms and schizophrenia. J Psychiatr Res 2003; 37: 457–462.

    Article  Google Scholar 

  13. Yu L, Yang MS, Zhao J, Shi YY, Zhao XZ, Yang JD et al. An association between polymorphisms of the interleukin-10 gene promoter and schizophrenia in the Chinese population. Schizophr Res 2004; 71: 179–183.

    Article  Google Scholar 

  14. Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC . Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res 2002; 57: 247–258.

    Article  Google Scholar 

  15. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001; 47: 13–25.

    Article  CAS  Google Scholar 

  16. Burdach S, Nishinakamura R, Dirksen U, Murray R . The physiologic role of interleukin-3, interleukin-5, granulocyte-macrophage colony-stimulating factor, and the beta c receptor system. Curr Opin Hematol 1998; 5: 177–180.

    Article  CAS  Google Scholar 

  17. Reddy EP, Korapati A, Chaturvedi P, Rane S . IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 2000; 19: 2532–2547.

    Article  CAS  Google Scholar 

  18. Chavany C, Vicario-Abejon C, Miller G, Jendoubi M . Transgenic mice for interleukin 3 develop motor neuron degeneration associated with autoimmune reaction against spinal cord motor neurons. Proc Natl Acad Sci USA 1998; 95: 11354–11359.

    Article  CAS  Google Scholar 

  19. Giralt M, Carrasco J, Penkowa M, Morcillo MA, Santamaria J, Campbell IL et al. Astrocyte-targeted expression of interleukin-3 and interferon-alpha causes region-specific changes in metallothionein expression in the brain. Exp Neurol 2001; 168: 334–346.

    Article  CAS  Google Scholar 

  20. Sugita Y, Zhao B, Shankar P, Dunbar CE, Doren S, Young HA et al. CNS interleukin-3 (IL-3) expression and neurological syndrome in antisense-IL-3 transgenic mice. J Neuropathol Exp Neurol 1999; 58: 480–488.

    Article  CAS  Google Scholar 

  21. Powell HC, Garrett RS, Brett FM, Chiang CS, Chen E, Masliah E et al. Response of glia, mast cells and the blood brain barrier, in transgenic mice expressing interleukin-3 in astrocytes, an experimental model for CNS demyelination. Brain Pathol 1999; 9: 219–235.

    Article  CAS  Google Scholar 

  22. Hanson DR, Gottesman II . Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 2005; 6: 7–24.

    Article  Google Scholar 

  23. Sirota P, Schild K, Elizur A, Djaldetti M, Fishman P . Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19: 75–83.

    Article  CAS  Google Scholar 

  24. Lencz T, Morgan TV, Athanasiou M, Dain B, Reed CR, Kane CR et al. Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007; 12: 572–580.

    Article  CAS  Google Scholar 

  25. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der HJ, Fiers W et al. A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell 1991; 66: 1175–1184.

    Article  CAS  Google Scholar 

  26. Geijsen N, Koenderman L, Coffer PJ . Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family. Cytokine Growth Factor Rev 2001; 12: 19–25.

    Article  CAS  Google Scholar 

  27. Martinez-Moczygemba M, Huston DP . Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol 2003; 112: 653–665.

    Article  CAS  Google Scholar 

  28. Takahashi S, Cui YH, Kojima T, Han YH, Zhou RL, Kamioka M et al. Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families. Am J Med Genet B Neuropsychiatr Genet 2003; 120: 11–17.

    Article  Google Scholar 

  29. D’Andrea RJ, Harrison-Findik D, Butcher CM, Finnie J, Blumbergs P, Bartley P et al. Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice. J Clin Invest 1998; 102: 1951–1960.

    Article  Google Scholar 

  30. Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman M, Walsh D . The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives. Arch Gen Psychiatry 1993; 50: 781–788.

    Article  CAS  Google Scholar 

  31. Kendler KS, Myers JM, O’Neill FA, Martin R, Murphy B, MacLean CJ et al. Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 2000; 157: 402–408.

    Article  CAS  Google Scholar 

  32. Endicott J, Andreasen N, Spitzer RL . Family History Research Diagnostic Criteria. New York State Psychiatric Institute: New York, 1978.

    Google Scholar 

  33. Livak KJ . Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999; 14: 143–149.

    Article  CAS  Google Scholar 

  34. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy – Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  Google Scholar 

  35. Martin ER, Monks SA, Warren LL, Kaplan NL . A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000; 67: 146–154.

    Article  CAS  Google Scholar 

  36. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Google Scholar 

  37. Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.

    CAS  Google Scholar 

  38. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2004; 21: 263–265.

    Article  Google Scholar 

  39. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  Google Scholar 

  40. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  Google Scholar 

  41. Yang J, Si T, Ling Y, Ruan Y, Han Y, Wang X et al. Association study between interleukin-1beta gene (IL-1beta) and schizophrenia. Life Sci 2003; 72: 3017–3021.

    Article  CAS  Google Scholar 

  42. Yao JK, Sistilli CG, van Kammen DP . Membrane polyunsaturated fatty acids and CSF cytokines in patients with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2003; 69: 429–436.

    Article  CAS  Google Scholar 

  43. Mazzarello V, Cecchini A, Fenu G, Rassu M, Dessy LA, Lorettu L et al. Lymphocytes in schizophrenic patients under therapy: serological, morphological and cell subset findings. Ital J Anat Embryol 2004; 109: 177–188.

    PubMed  Google Scholar 

  44. Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH . Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 1993; 150: 1408–1410.

    Article  CAS  Google Scholar 

  45. Ganguli R, Yang Z, Shurin G, Chengappa KN, Brar JS, Gubbi AV et al. Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry Res 1994; 51: 1–10.

    Article  CAS  Google Scholar 

  46. Naudin J, Capo C, Giusano B, Mege JL, Azorin JM . A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 1997; 26: 227–233.

    Article  CAS  Google Scholar 

  47. Naudin J, Capo C, Giusano B, Mege JL, Azorin JM . A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 1997; 26: 227–233.

    Article  CAS  Google Scholar 

  48. Levitt P, Ebert P, Mirnics K, Nimgaonkar VL, Lewis DA . Making the case for a candidate vulnerability gene in schizophrenia: convergent evidence for regulator of G-protein signaling 4 (RGS4). Biol Psychiatry 2006; 60: 534–537.

    Article  CAS  Google Scholar 

  49. Riley B, Kendler KS . Molecular genetic studies of schizophrenia. Eur J Hum Genet 2006; 14: 669–680.

    Article  CAS  Google Scholar 

  50. Williams NM, O’Donovan MC, Owen MJ . Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? Schizophr Bull 2005; 31: 800–805.

    Article  Google Scholar 

  51. Tosato S, Dazzan P, Collier D . Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophr Bull 2005; 31: 613–617.

    Article  Google Scholar 

  52. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 2007; 12: 74–86.

    Article  CAS  Google Scholar 

  53. Norton N, Williams HJ, Owen MJ . An update on the genetics of schizophrenia. Curr Opin Psychiatry 2006; 19: 158–164.

    Article  Google Scholar 

  54. Neale BM, Sham PC . The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353–362.

    Article  CAS  Google Scholar 

  55. Petryshen TL, Middleton FA, Kirby A, Aldinger KA, Purcell S, Tahl AR et al. Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 2005; 10: 366–374.

    Article  CAS  Google Scholar 

  56. McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D . A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2004; 2: 13–35.

    Article  Google Scholar 

  57. Halbreich U, Kahn LS . Hormonal aspects of schizophrenias: an overview. Psychoneuroendocrinology 2003; 28 (Suppl 2): 1–16.

    CAS  Google Scholar 

  58. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–1302.

    Article  CAS  Google Scholar 

  59. Tan EC, Chong SA, Wang H, Chew-Ping LE, Teo YY . Gender-specific association of insertion/deletion polymorphisms in the nogo gene and chronic schizophrenia. Brain Res Mol Brain Res 2005; 139: 212–216.

    Article  CAS  Google Scholar 

  60. Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A et al. Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 2005; 10: 470–478.

    Article  CAS  Google Scholar 

  61. Salem JE, Kring AM . The role of gender differences in the reduction of etiologic heterogeneity in schizophrenia. Clin Psychol Rev 1998; 18: 795–819.

    Article  CAS  Google Scholar 

  62. Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I . Estrogen and cytokines production—the possible cause of gender differences in neurological diseases. Curr Pharm Des 2005; 11: 1017–1030.

    Article  CAS  Google Scholar 

  63. Cahill L . Why sex matters for neuroscience. Nat Rev Neurosci 2006; 7: 477–484.

    Article  CAS  Google Scholar 

  64. Bourdeau V, Deschenes J, Metivier R, Nagai Y, Nguyen D, Bretschneider N et al. Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol 2004; 18: 1411–1427.

    Article  CAS  Google Scholar 

  65. Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L et al. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006; 16: 995–1004.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study is supported by a research grant (RO1MH41953) to KSK from the National Institute of Mental Health. We thank the patients and their families for participating in this study. The Northern Ireland Blood Transfusion Service assisted with the collection of control sample.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Q Chen, X Wang, K S Kendler & X Chen

  2. The Department of Psychiatry, The Queens University, Belfast, Northern Ireland

    F A O'Neill

  3. The Health Research Board, Dublin, Ireland

    D Walsh

  4. Washington VA Medical Center-Georgetown University Medical Center Schizophrenia Research Program, Washington, DC, USA

    A Fanous

Authors
  1. Q Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F A O'Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Fanous
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K S Kendler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Q., Wang, X., O'Neill, F. et al. Association study of CSF2RB with schizophrenia in Irish family and case – control samples. Mol Psychiatry 13, 930–938 (2008). https://doi.org/10.1038/sj.mp.4002051

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4002051

Keywords

This article is cited by

Search

Advanced search

Quick links