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

OBJECTIVES: 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. METHODS: We examined 646 subjects in 136 families with SZ, largely of European ancestry (EA), genotyping 26 SNPs in DTNBP1. RESULTS: 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. CONCLUSION: Our results provide evidence for an association of SZ with SNPs at the 3' end of DTNBP1 in the samples studied.

Neuregulin 1 (NRG1 ) and schizophrenia: analysis of a US family sample and the evidence in the balance.

BACKGROUND: Individual genome-wide linkage scans and meta-analyses support that one or more susceptibility genes for schizophrenia are located in chromosome 8p. A gene from this region, neuregulin 1 (NRG1 ), known to be involved with glutamatergic function, has been found to be associated in some studied samples. METHOD: We have examined a new combined schizophrenia sample with 136 schizophrenia families largely of European ancestry (EA) and 646 subjects with DNA. We genotyped 14 single nucleotide polymorphisms (SNPs) in NRG1 including those reported to comprise schizophrenia-associated haplotypes in Icelandic, Scottish, Irish, and Chinese Han populations. RESULTS: We found no evidence of association at a single-marker or a haplotypic level. We review methodological aspects of previous studies to enable us to put our findings into context. CONCLUSIONS: Our failure to find an association between NRG1 and schizophrenia might reflect different linkage disequilibrium (LD) patterns found in different populations, disease allelic heterogeneity, clinical heterogeneity of schizophrenia, or inadequate statistical power deriving from moderate sample size. NRG1, if a true gene for schizophrenia, accounts for a small fraction of the disease in most populations. The confirmation of NRG1 as a schizophrenia susceptibility gene will require studies with a comprehensive set of markers and in larger samples. The possibility remains that reports of NRG1 association might reflect false positives.