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

Gwyneth Zai, Daniel J. Müller, Jan Volavka, Pal Czobor, Jeffrey A. Lieberman, Herbert Y. Meltzer, James L. Kennedy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)171-182
Number of pages12
Issue number2
StatePublished - Oct 2006


  • Clozapine response
  • Clozapine-induced weight gain
  • Family-based association test (FBAT)
  • Schizophrenia
  • Transmission disequilibrium
  • Tumor necrosis factor-alpha (TNF-α)

ASJC Scopus subject areas

  • Pharmacology


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