A comprehensive genetic association and functional study of TNF in schizophrenia risk.
In view of prior reports suggesting associations between polymorphisms of the tumor necrosis factor gene (TNF) and schizophrenia, we sequenced all exons, introns and 7 kb flanking sequence at TNF in DNA pooled from 125 Caucasian schizophrenia cases and 200 controls. We identified 18 SNPs of which we selected and genotyped 8 among 244 cases and 276 controls. We detected no significant genotype or haplotype associations in the entire sample or in subgroups defined by gender or exposure to HSV1, HSV2, CMV, or Toxoplasma gondii. We used a dual-luciferase expression assay to quantify TNF expression driven by each common promoter haplotype in a neuroblastoma cell line. Three haplotypes drove significantly lower levels of TNF expression than the most common haplotype, including a haplotype with -308A, the allele reported to increase risk for schizophrenia (in contrast to earlier reports). We find no evidence to implicate TNF gene polymorphisms for schizophrenia risk in our sample.
Shirts
Brian H
BH
Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pennsylvania 15213, USA.
Bamne
Mikhil
M
Kim
Jung Jin
JJ
Talkowski
Michael
M
Wood
Joel
J
Yolken
Robert
R
Nimgaonkar
Vishwajit L
VL
D000328:Adult; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012306:Risk; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha