Family and case-control association study of the tumor necrosis factor-alpha (TNF-alpha) gene with schizophrenia and response to antipsychotic medication.
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-alpha) is considered an interesting candidate for genetic studies as overproduction of TNF-alpha, which may be genetically modulated, can influence neuron growth and proliferation. Moreover, the TNF-alpha 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.


CONCLUSIONS
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).


CONCLUSIONS
Overall, the G-308A polymorphism of the TNF-alpha gene does not appear to play a major role in SCZ but might be involved in antipsychotic response.
Zai
Gwyneth
G
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
Müller
Daniel J
DJ
Volavka
Jan
J
Czobor
Pal
P
Lieberman
Jeffrey A
JA
Meltzer
Herbert Y
HY
Kennedy
James L
JL
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016022:Case-Control Studies; D003024:Clozapine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009679:Nuclear Family; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014150:Antipsychotic Agents; D014409:Tumor Necrosis Factor-alpha; D003024:Clozapine