Evaluation of association of SNPs in the TNF alpha gene region with schizophrenia

Abstract

The association of the tumor necrosis factor alpha (TNFalpha) -G308A promoter polymorphism with schizophrenia has complemented clinical findings of increased levels of the TNFalpha cytokine in schizophrenic patients, with some support for a functional consequence of the variant. Our previous studies of genetic causes in schizophrenia supported findings of linkage to the major histocompatibility complex (MHC) region where the TNFalpha gene is located as well as association with the -G308A promoter polymorphism. While the common G-allele shows association in our sample, association with the A-allele has been reported by other groups. This suggests linkage disequilibrium (LD) rather than direct involvement in the disorder. In order to define LD of DNA variants with the disorder in this area, we analyzed 36 SNPs in a 165-kb region around this polymorphism. We detected nominally significant associations (P < 0.05) of three markers (including the -G308A promoter polymorphism) and multiple haplotypes with schizophrenia in our sample of 204 families (79 sib-pairs and 125 trios). The association is largely restricted to a 30 kb high LD region/block and should assist in the identification of a schizophrenia susceptibility gene within the block or elsewhere in the MHC.

Association of Tumor Necrosis Factor –308G/A Promoter Polymorphism with Schizophrenia and Bipolar Affective Disorder in a Polish Population

“…Although the authors tried to keep the same ethnic proportions in patient and control groups, a stratification effect cannot be excluded. Consecutive positive studies provided evidence for the opposite association -involvement of the -308G allele in the risk of SCH, which is similar to our results [39][40][41] . A Finnish study pointed out that -308G/G homozygosity was modestly associated with SCH only in male subjects [37] .…”

“…A recent Chinese study describing an association of -1031T/C promoter TNF polymorphism with age of onset of SCH may show the importance of such attempts [62] . Undoubtedly the most valuable study in this context has been a positive report published recently by an Australian group, which analyzed 36 very densely located SNPs from a 165-kb region around the -G308A polymorphic site using a family-based sample [41] . This study clearly shows that such haplotype-based studies are required for a reliable and replicable analysis.…”

“…An association was reported with SCH and different alleles or genotypes of TNF [36][37][38][39][40][41] , but there are also negative results [42][43][44][45][46][47][48][49][50][51][52] . Two meta-analyses did not indisputably determine the involvement of this polymorphism in schizophrenia susceptibility [42,53] .…”

Two-stage case–control association study of polymorphisms in rheumatoid arthritis susceptibility genes with schizophrenia

“…These two SNPs in NFKBIL1 were not associated with schizophrenia in their Caucasian samples of 236 patients and 240 control subjects. The study by Morar et al 21 analyzed 36 SNPs in a 165-kb region around tumor necrosis factor, including five SNPs in NFKBIL1. There were no significant associations of these five SNPs in NFKBIL1 with schizophrenia in their sample of 204 families (79 sib-pairs and 125 trios).…”

“…Our results are in line with the negative findings reported in the previous studies. 20,21 To draw a definitive conclusion that NFKBIL1 does not contribute to genetic susceptibility to schizophrenia, however, further studies using larger sample sizes and sufficient markers are required in different ethnic populations.…”