Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.

Abstract

A recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. 1 The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. 2 However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

“…In this study we sought to replicate association of AKT1 with schizophrenia in the ISHDSF, prompted by the susceptibility haplotype in this sample within the dysbindin (DTNBP1) gene (21). Although no single AKT1 marker showed association with disease, the data were consistent with global association of common alleles for selected SNP haplotypes including rs1130214, and a striking under-transmission of these haplotypes with the rare allele (T) at rs1130214.…”

Interleukin 3 and schizophrenia: the impact of sex and family history

“…As seen in several other studies of schizophrenia candidate genes, different samples tend to have different risk haplotypes, [38][39][40][41][42][43][44] including flipping of the risk and protective haplotypes of DTNBP1 gene between the ISHDSF 45 and German nuclear families 46 and other samples. 47,48 In this study, the two family samples identified the same risk and protective haplotypes, but in the case-control sample, the risk haplotype in the family samples become protective (underrepresented in the affected individuals).…”

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

“…We did see a trend towards association between dysbindin and better go/nogo performance. Interestingly, Fallgatter et al (2006), using a neurophysiological index of the same paradigm in a normal sample, also found evidence of association with two dysbindin SNP's previously associated with schizophrenia (Schwab et al, 2003;van den Oord et al, 2003). Investigation in a larger schizophrenia sample will be required to interpret the significance of these results.…”