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Dysbindin (DTNBP1) and the Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1): Main and Epistatic Gene Effects Are Potential Contributors to Schizophrenia Susceptibility

Neuropsychiatric Genetics Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College, Dublin, Ireland. /
Biological psychiatry (Impact Factor: 9.47). 02/2008; 63(1):24-31. DOI: 10.1016/j.biopsych.2006.12.025
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ABSTRACT The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching.
A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results.
We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing.
Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.

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    • "The altered ultrastructure of hippocampal synaptic vesicles might cause reduced neurotransmission and thereafter the schizophrenia-like symptoms observed in sdy mice (Chen et al., 2008; Feng et al., 2008; Wang et al., 2014). However, except for DTNBP1 and BLOC1S3, genes encoding other BLOC-1 subunits have no significant association with schizophrenia although an epistatic interaction between DTNBP1 and MUTED might exist (Morris et al., 2008). Currently, there is no support for MUTED as a susceptibility gene for schizophrenia (Gerrish et al., 2009). "
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    • "Consistent with such a role in the nervous system, both Dysbindin and Snapin appear to function in synaptic vesicle trafficking and may be involved in other synaptic membrane trafficking pathways. Interestingly, another component of the BLOC-1 complex, Muted, has recently been associated with schizophrenia (Morris et al., 2008; Ryder and Faundez, 2009). These findings underscore the intriguing possibility that defective synaptic membrane trafficking through components of the BLOC-1 complex in the context of homeostatic synaptic plasticity may contribute to the etiology of complex neuropsychiatric diseases like schizophrenia. "
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    • "The first two types of studies mentioned above (i and ii) have been discussed in recent reviews (Schwab and Wildenauer, 2009; Talbot et al., 2009). In short: large-scale genetic studies using a case-control design have failed to demonstrate genome-wide significance for any association between individual common variants in DTNBP1 and schizophrenia in the general population of European ancestry or African–Americans (Sanders et al., 2008; Shi et al., 2009); although it should be noted that these studies have not been designed to explore potential genetic heterogeneity (Maher et al., 2010), epistatic interactions between variants in two or more genes (Edwards et al., 2008; Morris et al., 2008), interactions between genetic variants and environmental factors (Nicodemus et al., 2008) or the possibility that the genetic link between DTNBP1 and the disease might be restricted to few families [reviewed by Psychiatric GWAS Consortium Steering Committee (2009)]. Nevertheless, decreased protein levels have been observed in hippocampus and prefrontal cortex of post-mortem brain samples from schizophrenic patients (Talbot et al., 2004; Tang et al., 2009a; Talbot et al., 2011), notably much more often than expected from the frequency of the allelic variants being considered as candidate risk factors of the disease. "
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