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

Background: 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. Methods: 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. 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. Conclusions: Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.