Characterisation of Genetic Variation in ST8SIA2 and Its Interaction Region in NCAM1 in Patients with Bipolar Disorder

Autor: Janice M. Fullerton, Peter R. Schofield, Alex D. Shaw, Warren Kaplan, Philip B. Mitchell, Anna Heath, Yash Tiwari
Rok vydání: 2014
Předmět:
Genetic Screens
Bipolar Disorder
Gene Identification and Analysis
lcsh:Medicine
Exon
Gene Order
Genotype
Medicine and Health Sciences
Cluster Analysis
lcsh:Science
Genetics
Multidisciplinary
Chromosome Mapping
High-Throughput Nucleotide Sequencing
Genomics
CD56 Antigen
Functional Genomics
3. Good health
Sequence Analysis
Research Article
medicine.medical_specialty
dbSNP
Sequence analysis
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
Molecular Genetics
Molecular genetics
Mental Health and Psychiatry
Genetic variation
medicine
Humans
Molecular Biology Techniques
Sequencing Techniques
Molecular Biology
Genetic Association Studies
Sequence Assembly Tools
Mood Disorders
Gene Expression Profiling
lcsh:R
Haplotype
Computational Biology
Genetic Variation
Reproducibility of Results
Biology and Life Sciences
Psychoses
Epistasis
Genetic
Molecular Sequence Annotation
Human Genetics
Genome Analysis
Sialyltransferases
Haplotypes
Genetic Loci
lcsh:Q
Zdroj: PLoS ONE
PLoS ONE, Vol 9, Iss 3, p e92556 (2014)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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