Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia

Abstract

Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008-.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.

Figure 1

TRANSMIT results with three-marker haplotypes. When diagnostic categories D1–D2 and the condition of one affected offspring per nuclear family per extended pedigree are used, a sliding window of three markers was tested, at two-marker overlaps. Below each (most significant) overtransmitted haplotype is the P value for that haplotype, the haplotype frequency, and the global P value (median value of 20 runs), derived by evaluation of the transmissions of all haplotypes at once. SNPs within the dysbindin gene are in boldface and are offset, and the location of the gene is shown below the haplotype frequencies. Interval Length = marker-to-marker distance (in bp); na = instances in which no individual haplotype (either over- or undertransmitted) resulted in P<.05.