Association Study of the Dystrobrevin-Binding Gene With Schizophrenia in Australian and Indian Samples

Abstract

Numerous studies have reported association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. However, the pattern of results is complex and to date, no specific risk marker or haplotype has been consistently identified. The number of single nucleotide polymorphisms (SNPs) tested in these studies has ranged from 5 to 20. We attempted to replicate previous findings by testing 16 SNPs in samples of 41 Australian pedigrees, 194 Australian cases and 180 controls, and 197 Indian pedigrees. No globally significant evidence for association was observed in any sample, despite power calculations indicating sufficient power to replicate several previous findings. Possible explanations for our results include sample differences in background linkage dis-equilibrium and/or risk allele effect size, the presence of multiple risk alleles upon different haplotypes, or the presence of a single risk allele upon multiple haplotypes. Some previous associations may also represent false positives. Examination of Caucasian HapMap phase II genotype data spanning theDTNBP1region indicates upwards of 40 SNPs are required to satisfactorily assess all nonredundant variation withinDTNBP1and its potential regulatory regions for association with schizophrenia. More comprehensive studies in multiple samples will be required to determine whether specificDTNBP1variants function as risk factors for schizophrenia.

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

“…265,[297][298][299] However, several studies have failed to confirm this asso ciation. [300][301][302] Again, as with many of the previously discussed genes, there were multiple inconsistencies in and failures to replicate the positively associated polymorphisms across studies. A recent meta-analysis of 12 studies suggested that there is only a weak association of 1 single nucleotide polymorphism (SNP) in DTNBP1 and schizophrenia and that associations of additional SNPs with the disorder may be the direct result of only 1 study.…”

<i>DTNBP1 (Dystrobrevin Binding Protein 1)</i> and Schizophrenia: Association Evidence in the 3′ End of the Gene

“…Patients with SZ were reported to have decreased DTNBP1 in the glutamatergic terminal of the hippocampus and dorsolateral prefrontal cortex [10] , and risk haplotypes for SZ were also shown to be associated with reduced DTNBP1 expression in human cerebral cortex [11] . Convergent effects of several putative SZ suscep- Gornick 2005 h :102 families ( table 1 ) [8,9,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] . Although a number of studies showed supportive evidence for the association between DTNBP1 and SZ, these reports also showed considerable disagreement between the associated markers, alleles, and haplotypes.…”

Mutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high‐resolution melting analysis

“…Following the initial report by Straub et al [2002], a large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia [Schwab et al, 2003;Van Den Bogaert et al, 2003;van den Oord et al, 2003;Funke et al, 2004;Kirov et al, 2004;Numakawa et al, 2004;Williams et al, 2004;Fallin et al, 2005;Fanous et al, 2005;Li et al, 2005;DeRosse et al, 2006;Tochigi et al, 2006;Duan et al, 2007;Tosato et al, 2007;Vilella et al, 2008] although there are also many negative findings [Morris et al, 2003;Van Den Bogaert et al, 2003;De Luca et al, 2005;Holliday et al, 2006;Joo et al, 2006;Bakker et al, 2007;Datta et al, 2007;Liu et al, 2007;Turunen et al, 2007;Wood et al, 2007]. The large volume of supportive genetic association data, in our view, continues to suggest that DTNBP1 is a schizophrenia susceptibility gene, but specific risk alleles have been not been implicated as causal.…”