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 δ or J statistics located the specific markers (δ: 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.
Departments of aPsychiatry
bEpidemiology and Public Health
dNeurobiology, Yale University School of Medicine, New Haven
eVA Connecticut Healthcare System, West Haven Campus
fDepartment of Psychiatry, University of Connecticut School of Medicine, Farmington, Connecticut
hDepartment of Psychiatry, Mount Sinai School of Medicine, New York, USA
Correspondence to Professor Joel Gelernter, MD, Yale University School of Medicine, VA Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA
Tel: +1 203 932 5711 ext 3590; fax: +1 203 937 4741; e-mail: firstname.lastname@example.org
Received 12 May 2008 Accepted 24 January 2009