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Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome mapped in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members -α, β, and γ -which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHα enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allelespecific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Background: The 22q13-linked gene synapsin III is a positional candidate gene for schizophrenia (SZ). One interesting synapsin III single nucleotide polymorphism (SNP), –196G/A, has been identified in the promoter region. The –196A allele results in a 6/8 base match to the core recognition octamer sequence for Oct-1, a member of the POU family of transcription factors. Objective: To determine whether or not the –196 SNP is associated with either SZ or bipolar disorder (BD). Methods: A case control comparison was used to determine whether or not differences in allele or genotype distribution occurred in patients with SZ and BD. Electromobility gel shift assay (EMSA) was used to determine whether the –196 SNP affected protein binding. Results: A trend towards significance was detected when the allele distribution was analyzed in Caucasian patients with SZ (n = 145; 191 controls) and a cohort of subjects from the Czech Republic with BD (n = 82; 94 controls). No association was found in bipolar patients from the United States (n = 127) or in African-American patients with SZ (n = 124; 133 controls). EMSA showed that the region encompassing the –196 SNP binds to a brain protein in an allele-specific manner. Conclusions: These data, while inconclusive, suggest that –196 SNP should be further investigated as a candidate for 22q13-linked SZ.

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