Association study of putative promoter polymorphisms in the neuroplastin gene and schizophrenia

A previous study revealed a number of methamphetamine (METH) and phencyclidine (PCP)-reactive tags in a rat brain through serial analysis of gene expression. The present study extends this previous study by investigating whether two genes, which deduced from METH/PCP-reactive tags, were identified as those encoding human transmembrane proteins of the immunoglobulin (Ig) superfamily, neuroplastin (NPTN) and basigin (BSG), confer genetic susceptibility to schizophrenia by analyzing single nucleotide polymorphisms (SNPs). There were nominally significant differences between the two groups in their allelic frequencies (T Ins/Del, chi2=4.910, d.f.=1, P=0.040) and genotypic distributions (T/T or T/Del, chi2=5.116, d.f.=1, P=0.036) of rs3840846 in the 5'-upstream of NPTN. The two groups differed significantly also in their allelic frequencies (G/T, chi2=4.229, d.f.=1, P=0.044), but not genotypic distributions of rs3743500 in the 5'-upstream of NPTN. The haplotypes constructed from the three SNPs (rs3840846, rs3826047 and rs3743500, in order) in the 5'-upstream of NPTN showed a significant association with schizophrenia (permutation P=0.036), in that T-G-T (permutation P=0.028) and del-G-G (permutation P=0.040) were under-represented and over-represented, respectively, in schizophrenia. A reporter construct driven by the 5'-upstream region containing any haplotype consisting of the three SNPs had substantial transcriptional activity. Notably, a reporter construct containing a haplotype T-G-T had significantly lower transcriptional activity as compared with one having a haplotype T-G-G or T-A-G. There was no significant difference between the two groups regarding allelic frequencies, genotypic distribution or the adopted SNP-combinatory haplotype for BSG. These results suggest that NPTN may be involved in genetic susceptibility to schizophrenia.