DTNBP1 And NRG1 Are Susceptibility Genes Of Schizophrenia In Han Chinese Population

Schizophrenia is a mental disorder that affects approximately 1% of the population with lifelong devastating consequences. Based on evidence for a major contribution of genetic factors, decades of extensive efforts have been dedicated to the search of DNA sequence variations that increase the risk to SCZ. However, the mode of transmission is complex and non-Mendelian. Several factors such as possible involvement of numerous interactive genes of minor effect, yet unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in SCZ quite unproductive. The main approaches used to identify susceptibility genes are linkage and linkage disequilibrium studies and the study of cytogenetic abnormalities associated with or linked to schizophrenia. For the past 20 years, many linkage studies have been reported but have failed as yet to produce unequivocal, replicated demonstrations of linkage, while for sporadic cases, linkage disequilibirium studies have been performed but the outcome of such studies has also been quite modest. However, in the last two years, because of the availability of thecomplete human genomic sequence, along with technology advances and cost reductions in SNP identification and genotyping and the coordination of genome-wide scans by world wide consortia, many promising chromosome regions now have support from multiple independent studies. With fine mapping in these regions, several research groups recently announced discovering of susceptibility genes of schizophrenia. The evidence for these genes being involved in the etiology of schizophrenia were statistically robust and also neurobiologically plausible. But before firm acceptance, unequivocal replications remain the top priority. In the present study, we supplied independent statistical support of two of these most promising susceptibility genes: 6p22.3 gene DTNBP1 (dystrobrevin-binding protein 1) and 8p12 gene NRG1 (Neuregulin 1), which might play a role in the etiology of schizophrenia in Chinese Han population.We performed family-based allelic association study of 5 SNPs within DTNBP1 gene in 233 Han Chinese trios. The genotyping assay used in this study combined kinetic (real-time quantitative) PCR with allele-specific amplification, in which primers were designed to specifically amplify the reference allele or its variant in separate PCR reactions. Although no individual SNP was significant at the P=0.05 level, transmission/disequilibrium test of their haplotypes with TRANSMIT v 2.5 revealed a significant association with the disease (global P=0.0007- 0.0009). As for NRG1, we report a result obtained from a case-control study in the Chinese population (540 schizophrenics, 279 controls). 13 microsatellites within the boundaries of the 5' exon of the NRG1 gene weregenotyped by fluorescence microsatellite electrophoresis on MegaBACE 1000 instruments. Based on the LD pattern of this region, the result from the haplotype analysis indicated that two adjoining regions were associated with schizophrenia (T2 X2=57.8, 19df, P=0.00003; T2 X2=49.23, 19df, P=0.000267, using CLUMP). Along with the data obtained from the previous genetic studies in European samples, our findings suggest that the DTNBP1 and NRG1 gene might influence susceptibility to schizophrenia in Han Chinese population.