A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case–control and family-based sample of German ancestry

Abstract

Background Dysbindin (DTNBP1) is a widely-studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity. Method Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent-offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene-gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. Results No association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pairwise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pairwise comparisons. Conclusions Our results, based on one of the largest sample of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions.

Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia

“…As of 2008, there have been 45 follow-up association studies, 18 of them with positive results, which are annotated in the Schizophrenia Gene Database (Allen et al, 2008). A large, recent case-control study and family-based sample of German ancestry failed to find an association between DTNBP1 (38 SNPs genotyped) and schizophrenia (Strohmaier et al, 2010). Meta-analysis of DTNBP1 (rs1011313) yielded significant summary odds ratios suggesting a nominally significant increase in risk for schizophrenia (Allen et al, 2008).…”

“…Although there are inconsistencies in the reported alleles/haplotypes between studies (Desbonnet et al, 2009), the associations do cluster in 8 commonly typed SNPs that yield 6 common haplotypes (Riley et al, 2009). These inconsistent findings have triggered skepticism towards their validity for several reasons (Mutsuddi et al, 2006): the DTNBP1 haplotypes associated with schizophrenia have differed among studies, the same SNPs have not been genotyped in every association study, causal variants that might contribute to schizophrenia have not been found, and a demonstrated function associated with any of the risk haplotypes has not been identified (Strohmaier et al, 2010). DTNBP1 has also been associated with other illnesses including bipolar disorder and Hermansky-Pudlak syndrome type 7, a complex genetic disorder related to lysosome biogenesis (Li et al, 2003).…”

Current Strategies in Diagnosis of Inherited Storage Pool Defects

“…However, pulmonary function and computed tomography (CT) chest scans were normal [38]. Interestingly, DTNBP1 (dystrobrevin-binding protein 1, HPS7) gene variants were shown to be associated with schizophrenia; however, this correlation is controversial [39,40]. A Pakistani family with several HPS8 patients, all carrying the same mutation, did not demonstrate further clinical complications except Sandrock/Zieger ondary wave of platelet aggregation is impaired and platelets show an increased ATP-to ADP-ratio and a decreased amount of serotonin and calcium.…”

The DTNBP1 (dysbindin-1) gene variant rs2619522 is associated with variation of hippocampal and prefrontal grey matter volumes in humans

“…Since then (and even before), numerous investigations have been realized to verify the role of DTNBP1 as a schizophrenia susceptibility gene. While many genetic studies could replicate the association of DTNBP1 with schizophrenia [17, 34, 55, 61, 71, 74, 75, 83, 87], others failed to confirm the finding of Straub and colleagues [50, 51, 67]. A meta-analysis authored by Li & He in 2007 only found a weak association of DTNBP1 with schizophrenia [36].…”