Analysis of polymorphisms in AT-rich domains of neuregulin 1 gene in schizophrenia

Linkage analysis and association studies have pointed to neuregulin 1 (NRG1) as the prime candidate for 8p-linked schizophrenia (SZ). However, so far, no specific functional alleles in the gene's exons, intron-exon junctions and promoters have been identified that are unequivocally associated with SZ. In this study, we analyzed several NRG1 polymorphisms that affect ATTT motifs and AT-rich regions of the gene. We have previously identified a number of such polymorphisms in the promoters of other SZ and bipolar disorder (BD) candidate genes and found positive associations to several of them. In addition, allele specific differences in the binding of brain proteins have been found for many of the polymorphisms. A case control design was used to compare allele frequencies in Caucasian and African American patients with SZ and controls. In the African American group, a significant difference was found in the allele and genotype distribution for several of the markers and haplotype blocks located in the 5'- and X-ends of the gene. The most significant result was obtained for rs6150532, an insertion/deletion variant in a conserved region of an intron that separates two small, alternatively spliced exons. Allele-specific and developmental differences were detected in the binding of a brain protein using newborn rat pups when probes containing the two rs6150532 alleles were used in electromobility gel shift assays. There were no significant differences in allele or genotype distribution found for any of the markers in the Caucasian sample. Although the samples size is relatively small, the findings support a role for NRG1 in SZ in African Americans and suggest that polymorphic differences in regions of the gene that recognize AT-binding proteins may be a factor in disease pathogenesis. (C) 2005 Wiley-Liss, Inc.