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Family and case–control association study of the tumor necrosis factor-alpha (TNF-α) gene with schizophrenia and response to antipsychotic medication

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Abstract

Background

Dysregulation of the immune system has been suggested to play a role in the etiology of schizophrenia (SCZ). In this context, the tumor necrosis factor-alpha (TNF-α) is considered an interesting candidate for genetic studies as overproduction of TNF-α, which may be genetically modulated, can influence neuron growth and proliferation. Moreover, the TNF-α gene is located on chromosome 6p21.3, a region that has been found to be associated with SCZ in numerous linkage studies. One functional polymorphism, G-308A, has been studied for association with SCZ yielding inconsistent findings.

Results and discussions

In our study, we investigated the G-308A polymorphism with SCZ including 95 nuclear families and 149 pairs of cases/controls matched by age, gender, and ethnicity. Furthermore, we examined BPRS change scores (after 6 weeks, 3 months, and 6 months) and weight changes (after 6 weeks) with this polymorphism in 153 and 247 patients, respectively, after clozapine treatment. We did not observe biased transmission using family-based association test (P=0.752) or significant differences in case/control studies (P=0.839). However, patients with allele A showed significant improvement on BPRS change score after 3 months (t=2.000, P=0.049) and 6 months (t=2.481, P=0.015) of clozapine treatment when compared with patients without allele A. Moreover, trends were observed for genotype A/A with clinical improvement in BPRS change score after 6 months (F=2.834, P=0.065) using ANCOVA, and for allele G with weight gain (t=−1.702, P=0.091).

Conclusion

Overall, the G-308A polymorphism of the TNF-α gene does not appear to play a major role in SCZ but might be involved in antipsychotic response.

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Acknowledgements

This work has been supported by the Ontario Graduate Scholarship (GZ), the Institute of Medical Science Continuing Award (GZ), and the Canadian Institutes of Health Research (CIHR) postdoctoral fellowship award (DJM). Gwyneth Zai and Daniel J. Müller have contributed equally to this work.

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Authors and Affiliations

  1. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada

    Gwyneth Zai, Daniel J. Müller & James L. Kennedy

  2. Institute of Medical Science, University of Toronto, Toronto, Canada

    Gwyneth Zai & James L. Kennedy

  3. Department of Psychiatry, University Medicine Berlin, Campus Charité Mitte, Berlin, Germany

    Daniel J. Müller

  4. Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Jan Volavka & Pal Czobor

  5. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    Jan Volavka & Pal Czobor

  6. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeffrey A. Lieberman

  7. Psychiatric Hospital at Vanderbilt, Nashville, TN, USA

    Herbert Y. Meltzer

  8. Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada

    James L. Kennedy

  9. Neuroscience Department, Centre for Addiction and Mental Health, Toronto, Canada

    James L. Kennedy

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  1. Gwyneth Zai
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  2. Daniel J. Müller
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  3. Jan Volavka
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  4. Pal Czobor
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  7. James L. Kennedy
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Correspondence to James L. Kennedy.

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Zai, G., Müller, D.J., Volavka, J. et al. Family and case–control association study of the tumor necrosis factor-alpha (TNF-α) gene with schizophrenia and response to antipsychotic medication. Psychopharmacology 188, 171–182 (2006). https://doi.org/10.1007/s00213-006-0482-4

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