Association study of neuregulin 1 gene with schizophrenia

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Abstract
A number of studies have indicated that 8p22-p12 is likely to harbor schizophrenia susceptibility loci. In this region, the candidate gene of interest, neuregulin 1 (NRG1), may play a role in the pathogenesis of schizophrenia. Then in the present study, we performed the linkage disequilibrium to determine the association between three genetic variants (SNPs: rs3924999, rs2954041, SNP8NRG221533) on NRG1 gene and schizophrenia in 246 Chinese Han schizophrenic family trios using PCR-based restriction fragment length polymorphism method and denaturing high-performance liquid chromatography. The transmission disequilibrium test analysis for each variant showed a significant difference between two transmitted alleles even after Bonferroni correction (rs3924999, P ¼ 0.007752; rs2954041, P ¼ 0.0009309; SNP8NRG221533, P ¼ 0.012606). The global v2 test for haplotype transmission also revealed a strong association (v2 ¼ 46.068, df ¼ 7, Po0.000001). Our results suggest that the NRG1 gene may play a role in conferring susceptibility to the disease. Molecular Psychiatry (2003) 8, 706-709. doi:10.1038/sj.mp.4001377 Schizophrenia is a complex disease, a common mental disorder with a prevalence of 0.5-1% in the general population. It is clinically characterized by disturbed thought processes, delusions, hallucina- tions, and/or reduced social skills.1 A number of studies indicate a genetic component contributing to schizophrenia, but the mode of inheritance does not follow a simple Mendelian pattern. In spite of the failure to identify a schizophrenia gene of major import in multiply affected families, more than one data set from genome-wide scans provides convincing evidence that 8p22-p21 may harbor candidate genes which may confer susceptibility to schizophrenia to an individual.2-5 Interestingly, two studies carried out by Stefansson et al6,7 reported that the gene coding for neuregulin 1 (NRG1) was located in 8p21; its position as well as function strongly supported NRG1 gene as a susceptibility gene for schizophrenia. In their study, however, they had not found a clear pathogenic mutation. Several dozens of single nucleotide poly- morphisms (SNPs) have been identified within the locus (http://www.ncbi.nlm.nih.gov/SNP/), of which we randomly selected two that can be detected by the restriction fragment length polymorphism (RFLP) analysis. Of the two SNPs, one SNP (rs3924999, G38A), a G to A base change, occurs in position 12 within the second exon of the NRG1 gene, and the database (http://www.ncbi.nlm.nih.gov/SNP/) shows that the SNP changes the amino acid from arginine (Arg) to glutamine (Gln) (Arg 38 Gln). Another SNP (rs2954041), located in fifth intron, may still be informative, for example, by being in linkage dis- equilibrium with a causal locus for schizophrenia. Therefore, it is valuable to investigate the possibility that these polymorphism sites on the NRG1 locus may be associated with schizophrenia. We also genotyped the single most significant SNP (SNP8NRG221533) described in Stefansson's findings6,7 by denaturing high-performance liquid chromatography (dHPLC) in order to clarify the similarities or differences of SNP8NRG221533 polymorphism in the different populations. In the present study, we conducted association analysis to determine the relationship between NRG1 gene and schizophrenia. As the transmission dis- equilibrium test (TDT), which evaluates allele trans- missions from heterozygous parents to affected individuals, provides an index of association which is unbiased by population structure. Therefore, we performed a family-based test in the present study. We analyzed the three polymorphisms of NRG1 gene in 246 Chinese Han schizophrenic family trios by the PCR-based RFLP and dHPLC. The genotype distribu- tions and allelic frequencies are presented in Table 1. The TDT analysis for each locus showed a significant difference between two transmitted alleles (Table 2) even after Bonferroni correction (rs3924999, P ¼ 0.007752; rs2954041, P ¼ 0.0009309; SNP8NRG221533,