Characterisation of Genetic Variation in <i>ST8SIA2</i> and Its Interaction Region in NCAM1 in Patients with Bipolar Disorder

<div><p>Alpha-2,8-sialyltransferase 2 (ST8SIA2) is an enzyme responsible for the transfer of polysialic acid (PSA) to glycoproteins, principally the neuronal cell adhesion molecule (NCAM1), and is involved in neuronal plasticity. Variants within <i>ST8SIA2</i> have previously shown association with bipolar disorder, schizophrenia and autism. In addition, altered PSA-NCAM expression in brains of patients with schizophrenia or bipolar disorder indicates a functional dysregulation of glycosylation in mental illness. To explore the role of sequence variation affecting PSA-NCAM formation, we conducted a targeted re-sequencing study of a ∼100 kb region – including the entire ST8SIA2 gene and its region of interaction with NCAM1 – in 48 Caucasian cases with bipolar disorder using the Roche 454 platform. We identified over 400 DNA variants, including 47 putative novel variants not described in dbSNP. Validation of a subset of variants via Sequenom showed high reliability of Roche 454 genotype calls (97% genotype concordance, with 80% of novel variants independently verified). We did not observe major loss-of-function mutations that would affect PSA-NCAM formation, either by ablating ST8SIA2 function or by affecting the ability of NCAM1 to be glycosylated. However, we identified 13 SNPs in the UTRs of <i>ST8SIA2</i>, a synonymous coding SNP in exon 5 (rs2305561, P207P) and many additional non-coding variants that may influence splicing or regulation of <i>ST8SIA2</i> expression. We calculated nucleotide diversity within <i>ST8SIA2</i> on specific haplotypes, finding that the diversity on the specific “risk” and “protective” haplotypes was lower than other non-disease-associated haplotypes, suggesting that putative functional variation may have arisen on a spectrum of haplotypes. We have identified common and novel variants (rs11074064, rs722645, 15∶92961050) that exist on a spectrum of haplotypes, yet are plausible candidates for conferring the effect of risk and protective haplotypes via multiple enhancer elements. A Galaxy workflow/pipeline for sequence analysis used herein is available at: <a href="https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources" target="_blank">https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources</a>.</p>