NCAM1 association study of bipolar disorder and schizophrenia: polymorphisms and alternatively spliced isoforms lead to similarities and differences

Objective: The neural cell adhesion molecule (NCAM1) is a multifunction transmembrane protein involved in synaptic plasticity, neurodevelopment, and neurogenesis. Multiple NCAM1 proteins were differentially altered in bipolar disorder and schizophrenia. Single nucleotide polymorphisms (SNPs) in the NCAM1 gene were significantly associated with bipolar disorder in the Japanese population. Bipolar disorder and schizophrenia may share common vulnerability or susceptibility risk factors for shared features in each disorder. Methods: Both SNPs and splice variants in the NCAM1 gene were analysed in bipolar disorder and schizophrenia. A case-control study design for association of SNPs and differential exon expression in the NCAM1 gene was used. Results: A genotypic association between bipolar disorder and SNP b (rs2303377 near mini-exon b) and a suggestive association between schizophrenia and SNP 9 (rs646558) were found. Three of the two marker haplotypes for SNP 9 and SNP b showed varying frequencies between bipolar and controls (P < 0.0001) as well as between schizophrenia and controls (P < 0.0001). There were nine NCAM1 transcripts present in postmortem brain samples that involve alternative splicing of NCAM1 mini-exons (a, b, c) and the secreted (SEC) exon. Significant differences in the amounts of four alternatively spliced isoforms were found between NCAM1 SNP genotypes. In exploratory analysis, the c-SEC alternative spliced isoform was significantly decreased in bipolar disorder compared to controls for NCAM1 SNP b heterozygotes (P=0.013). Conclusions: Diverse NCAM1 transcripts were found with possibly different functions. The results suggest that SNPs within NCAM1 contribute differential risk for both bipolar disorder and schizophrenia possibly by alternative splicing of the gene.