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
ST8SIA2 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
ST8SIA2, a synonymous coding SNP in exon 5 (rs2305561, P207P) and many additional non-coding variants that may influence splicing or regulation of
ST8SIA2 expression. We calculated
nucleotide diversity within
ST8SIA2 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: https://main.g2.bx.psu.edu/u/a-shaw-neura/p/next-generation-resources.