Comprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes

In a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25p24. The 6p region contains Dysbindin DTNBP1, considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic reexamination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1and its association with schizophrenia, using a HapMapbased genetagging approach. We genotyped 39 tSNPs in a sample of 336 cases and 172 controls of AngloIrish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control sample were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5′ region. Neither global haplotype tests, nor specific analysis of the “risk” haplotype previously reported in an ethnically related population, the Irish highdensity schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our sample. The framework and results of this study should facilitate further attempts at reanalysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation. © 2008 WileyLiss, Inc.