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DTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3' end of the gene.

ABSTRACT: Dysbindin (DTNBP1) has been identified as a susceptibility gene for schizophrenia (SZ) through a positional approach. However, a variety of single nucleotide polymorphisms (SNPs) and haplotypes, in different parts of the gene, have been reported to be associated in different samples, and a precise molecular mechanism of disease remains to be defined. We have performed an association study with two well-characterized family samples not previously investigated at the DTNBP1 locus.We examined 646 subjects in 136 families with SZ, largely of European ancestry (EA), genotyping 26 SNPs in DTNBP1.Three correlated markers (rs875462, rs760666, and rs7758659) at the 3' region of DTNBP1 showed evidence for association to SZ (p = 0.004), observed in both the EA (p = 0.031) and the African American (AA) subset (p = 0.045) with the same over-transmitted allele. The most significant haplotype in our study was rs7758659-rs3213207 (global p = 0.0015), with rs3213207 being the most frequently reported associated marker in previous studies. A non-conservative missense variant (Pro272Ser) in the 3' region of DTNBP1 that may impair DTNBP1 function was more common in SZ probands (8.2%) than in founders (5%) and in dbSNP (2.1%), but did not reach statistical significance.Our results provide evidence for an association of SZ with SNPs at the 3' end of DTNBP1 in the samples studied.

SUBMITTER: Duan J

PROVIDER: S-EPMC2861529 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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DTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3' end of the gene.

Duan Jubao J Martinez Maria M Sanders Alan R AR Hou Cuiping C Burrell Gregory J GJ Krasner Aaron J AJ Schwartz Daniel B DB Gejman Pablo V PV

Human heredity 20070502 2

<h4>Objectives</h4>Dysbindin (DTNBP1) has been identified as a susceptibility gene for schizophrenia (SZ) through a positional approach. However, a variety of single nucleotide polymorphisms (SNPs) and haplotypes, in different parts of the gene, have been reported to be associated in different samples, and a precise molecular mechanism of disease remains to be defined. We have performed an association study with two well-characterized family samples not previously investigated at the DTNBP1 locu ...[more]

PMID: 17476109

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Project description:BACKGROUND:Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods. METHODS:Six markers at DTNBP1 were genotyped by mass spectroscopy ('MassARRAY' technique) in a sample of 663 individuals, including 346 healthy individuals European-Americans (EAs) and 48 African-Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method). RESULTS:Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC/GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using d or J statistics located the specific markers (d: P1328; J: P1333) closest to the putative risk sites in EAs. CONCLUSION:This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

Dataset Information

DTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3' end of the gene.

Publications

DTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3' end of the gene.

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