A case control and family based association study of the neuregulin1 gene and schizophrenia.

D ata from twin, family, and adoption studies provide strong evidence that genetic factors play a major aetiological role in schizophrenia. By a series of linkage studies, chromosome 8p has been implicated as a region harbouring a schizophrenia susceptibility gene. Recently, Stefansson and colleagues reported that neuregulin 1 (NRG1), located in 8p21-12, may be involved in the aetiology of schizophrenia. 5 In their linkage and association studies, a 290 kb core at risk haplotype at the 59 end of NRG1 was found to be strongly associated with schizophrenia in Icelandic and Scottish populations. This haplotype contains the first exon of NRG1, which encodes a part of glial growth factor 2 (GGF2). Deficiency of glial growth factors has been presumed to be implicated in the pathogenesis of schizophrenia. Futhermore, NRG1 mutant mice have fewer functional N-methyl D-aspartate(NMDA) receptors than wild type mice, and display stereotypic behavioural abnormalities similar to those of normal mice treated with the psychogenic drug phenylcyclidine. This core at risk haplotype was defined by five single nucleotide polymorphisms (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, SNP8NRG433E1006) and two microsatellites (478B14-848, 420M91395). The frequency of this haplotype in schizophrenic individuals was higher than in controls; in Icelandic samples the frequency was 15.4 (7.5%; p = 0.000087). The first replication using Scottish samples revealed a similar result at 10.2 (5.9%; p = 0.00031). Another replication performed by Williams et al with British or Irish samples used one SNP and the two microsatellites of the core at risk haplotype. However, the association was much weaker at 9.5 (7.5%; p = 0.04). Yang et al reported other markers located in the middle of NRG1 and associated with schizophrenia, in a Chinese population. Another independent analysis using 13 microsatellites found two groups of haplotypes, which were significantly associated with schizophrenia, in a Chinese population. All these studies suggest that NRG1 may be a susceptibility gene for schizophrenia. However, there are differences in the findings and more replications are needed. Here we present results from the haplotype analysis using both case control and TDT. In our studies, only three of the five SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177) and the two microsatellites reported by Stefansson et al were genotyped. The marker SNP8NRG221132 was abandoned because of low heterozygosity. We genotyped more than 200 individuals at this locus, but no allele A was found. In all, 1724 Han people Chinese participated in our research, including 369 subjects with schizophrenia, 299 controls in the case control study, and 352 family trios in the TDT study.