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 Research Article
  • Published:

Tumor necrosis factor receptor-II: heritability and effect on brain morphology in schizophrenia

Abstract

A growing body of research suggests the involvement of immune system factors in central nervous system development and in pathophysiology related to schizophrenia. 1, 2 We therefore investigated the Tumor Necrosis Factor Receptor-II (TNF-RII), a TNFα receptor expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the relationship between TNF-RII and adult brain morphology. The study sample consisted of 140 probands diagnosed with schizophrenia or schizophreniform disorder, 197 parents of the probands (a subset of which formed 62 proband-parent trios), and 46 psychiatrically normal control subjects. A bi-allelic TNF-RII polymorphism was examined for evidence of association, with none being found between this polymorphism and schizophrenia. Subjects with schizophrenia homozygous for allele 1, however, had larger ventricles and smaller frontal lobes than subjects with at least one copy of allele 2. On follow-up testing, they also had an earlier, less variable age of onset for their illness. We found no support, therefore, for TNF-RII as a disease susceptibility gene for schizophrenia. The gene may, however, modify phenotypic aspects of the disease such as brain morphology and age of onset of illness.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Muller N, Ackenheil M . Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 1–33

    Article  CAS  Google Scholar 

  2. Zhao B, Schwartz JP . Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives J Neurosci Res 1998; 52: 7–16

    Article  CAS  Google Scholar 

  3. Merrill JE . Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological Dev Neurosci 1992; 14: 1–10

    Article  CAS  Google Scholar 

  4. Munoz-Fernandez MA, Fresno M . The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system Prog Neurobiol 1998; 56: 307–340

    Article  CAS  Google Scholar 

  5. De Simoni MG, Imeri L . Cytokine-neurotransmitter interactions in the brain Biol Signals Recept 1998; 7: 33–44

    Article  CAS  Google Scholar 

  6. Monteleone P, Fabrazzo M, Tortorella A, Maj M . Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment Psychiatry Res 1997; 71: 11–17

    Article  CAS  Google Scholar 

  7. Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H . Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients Eur Arch Psychiatry Clin Neurosci 1996; 246: 279–284

    Article  CAS  Google Scholar 

  8. 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 

  9. Rothwell NJ, Luheshi G, Toulmond S . Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology Pharmacol Ther 1996; 69: 85–95

    Article  CAS  Google Scholar 

  10. Andreasen NC, Flashman L, Flaum M, Arndt S, Swayze VN, O'Leary DS et al. Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging Jama 1994; 272: 1763–1769

    Article  CAS  Google Scholar 

  11. Pearlson GD, Marsh L . Structural brain imaging in schizophrenia: a selective review Biol Psychiatry 1999; 46: 627–649

    Article  CAS  Google Scholar 

  12. Bilder RM, Wu H, Bogerts B, Degreef G, Ashtari M, Alvir JM et al. Absence of regional hemispheric volume asymmetries in first-episode schizophrenia Am J Psychiatry 1994; 151: 1437–1447

    Article  CAS  Google Scholar 

  13. Nopoulos P, Torres I, Flaum M, Andreasen NC, Ehrhardt JC, Yuh WT . Brain morphology in first-episode schizophrenia Am J Psychiatry 1995; 152: 1721–1723

    Article  CAS  Google Scholar 

  14. Campbell IL . Transgenic mice and cytokine actions in the brain: bridging the gap between structural and functional neuropathology Brain Res Brain Res Rev 1998; 26: 327–336

    Article  CAS  Google Scholar 

  15. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors Nature Med 1996; 2: 788–794

    Article  CAS  Google Scholar 

  16. Vargas F, Tolosa E, Sospedra M, Catalfamo M, Lucas-Martin A, Obiols G et al. Characterization of neural cell adhesion molecule (NCAM) expression in thyroid follicular cells: induction by cytokines and over-expression in autoimmune glands Clin Exp Immunol 1994; 98: 478–488

    Article  CAS  Google Scholar 

  17. Rothwell NJ, Luheshi GN . Brain TNF: damage limitation or damaged reputation? Nature Med 1996; 2: 746–747

    Article  CAS  Google Scholar 

  18. Cheng B, Christakos S, Mattson MP . Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis Neuron 1994; 12: 139–153

    Article  CAS  Google Scholar 

  19. Rink L, Kirchner H . Recent progress in the tumor necrosis factor-alpha field Int Arch Allergy Immunol 1996; 111: 199–209

    Article  CAS  Google Scholar 

  20. Jarskog LF, Xiao H, Wilkie MB, Lauder JM, Gilmore JH . Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro Int J Dev Neurosci 1997; 15: 711–716

    Article  CAS  Google Scholar 

  21. Vandanabeele P, DePercq W, Beyaert R, Fiers W . Two tumour necrosis factor receptors: structure and functions Trends Biochem Sci 1995; 5: 392–399

    Google Scholar 

  22. Ando T, Dunn AJ . Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice Neuroimmunomodulation 1999; 6: 319–329

    Article  CAS  Google Scholar 

  23. Hayley S, Brebner K, Lacosta S, Merali Z, Anisman H . Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations J Neurosci 1999; 19: 5654–5665

    Article  CAS  Google Scholar 

  24. Dunn AJ, Wang J, Ando T . Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress Adv Exp Med Biol 1999; 461: 117–127

    Article  CAS  Google Scholar 

  25. Silverman JM, Smith CJ, Guo SL, Mohs RC, Siever LJ, Davis KL . Lateral ventricular enlargement in schizophrenic probands and their siblings with schizophrenia-related disorders Biol Psychiatry 1998; 43: 97–106

    Article  CAS  Google Scholar 

  26. Cannon TD, van Erp TGM, Huttunen M, Lonnqvist J, Salonen O, Valanne L et al. Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenia patients, their siblings, and controls Arch Gen Psychiatry 1998; 55: 1084–1091

    Article  CAS  Google Scholar 

  27. Shihabuddin L, Silverman JM, Buchsbaum MS, Seiver LJ, Luu C, Germans MK et al. Ventricular enlargement associated with linkage marker for schizophrenia-related disorders in one pedigree Mol Psychiatry 1996; 1: 215–222

    CAS  PubMed  Google Scholar 

  28. Wassink TH, Nelson JJ, Crowe RR, Andreasen NC . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia Am J Med Genet 1999; 88: 724–728

    Article  CAS  Google Scholar 

  29. Andreasen NC, Flaum M, Arndt S . The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology Arch Gen Psychiatry 1992; 49: 615–623

    Article  CAS  Google Scholar 

  30. Rau H, Donner H, Usadel KH, Badenhoop K . Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin-dependent diabetes mellitus or Grave's disease Tissue Antigens 1997; 49: 535–536

    Article  CAS  Google Scholar 

  31. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993; 52: 506–516

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Andreasen NC, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K et al. Image processing for the study of brain structure and function: problems and programs J Neuropsychiatry Clin Neurosci 1992; 4: 125–133

    Article  CAS  Google Scholar 

  33. Andreasen NC, Cizadlo T, Harris G, Swayze Vd, O'Leary DS, Cohen G et al. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging J Neuropsychiatry Clin Neurosci 1993; 5: 121–130

    Article  CAS  Google Scholar 

  34. Magnotta VA, Heckel D, Andreasen NC, Cizadlo T, Corson PW, Ehrhardt JC et al. Measurement of brain structures with artificial neural networks: two- and three-dimensional applications Radiology 1999; 211: 781–790

    Article  CAS  Google Scholar 

  35. Woods RP, Cherry SR, Mazziotta JC . Rapid automated algorithm for aligning and reslicing PET images J Comput Assist Tomogr 1992; 16: 620–633

    Article  CAS  Google Scholar 

  36. Harris G, Andreasen NC, Cizadlo T, Bailey JM, Bockholt J, Magnotta V et al. Improving tissue classification in magnetic resonance imaging: a three-dimensional multispectral discriminant analysis method with automated training class selection J Comput Assist Tomogr 1999; 23: 144–154

    Article  CAS  Google Scholar 

  37. Talairach J, Tournoux P . Co-planar Stereotaxic Atlas of the Human Brain Theime: New York 1988

    Google Scholar 

  38. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VWn, Flashman LA et al. Automatic atlas-based volume estimation of human brain regions from MR images J Comput Assist Tomogr 1996; 20: 98–106

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by NIMH grants MH43212 and MH00735 (RRC), and MH-31593 and MH-40856 (NCA); MHCRC grant MH-43271; the Nellie Ball Trust Research Fund (Iowa State Bank and Trust Company, Trustee); and a NARSAD Young Investigator Award.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T H Wassink.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wassink, T., Crowe, R. & Andreasen, N. Tumor necrosis factor receptor-II: heritability and effect on brain morphology in schizophrenia. Mol Psychiatry 5, 678–682 (2000). https://doi.org/10.1038/sj.mp.4000807

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000807

Keywords

This article is cited by

Search

Quick links