Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26
Open accessAbstract
We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n = 385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P = 0.0043; rs2168351, P = 0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls = 0.41 vs 0.31; χ(2) = 6.46, P = 0.011, OR = 1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n = 256) (χ(2) = 8.41, P = 0.004, OR = 1.82). Using GWAS data from the NIMH bipolar disorder (n = 2055) and NIMH schizophrenia (n = 2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (χ(2) = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ(2) = 2.3, P = 0.129, OR = 1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87) = 6.031, P = 0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults.
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- Authors
- McAuley, E. Z., Scimone, A., Tiwari, Y., Agahi, G., Mowry, B. J., Holliday, E. G., Donald, J. A., Weickert, C. S., Mitchell, P. B., Schofield, P. R., & Fullerton, J. M.
- Affiliations
- UNSW Sydney (AU)
- Neuroscience Research Australia (AU)
- The University of Queensland (AU)
- Queensland Centre for Mental Health Research (AU)
- Macquarie University (AU)
- Corresponding author
- Schofield, Peter R.
- Fullerton, Janice M.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-31
- Volume
- 7
- Issue
- 5
- Pages
- e38172
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3364966
- OpenAlex
- W2062251431
- Cited by
- 82
- References
- 47
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 3 · 2016: 11 · 2015: 5 · 2014: 9 · 2013: 10
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Stanley Medical Research Institute
- University of California, San Diego
- Medical Research Council
- National Health and Medical Research Council (510135, 157209, 630574, 325643, 325641, 510216)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- ST8SIA2, bipolar spectrum disorders, schizophrenia, mood disorders, psychosis, genetic susceptibility, risk haplotype, single nucleotide polymorphisms, glycosylation
- MeSH terms
- Adult, Base Sequence, Bipolar Disorder, Chromosome Mapping, Chromosomes, Human, Pair 15, Female, Haplotypes, Humans, Male, Middle Aged, Psychotic Disorders, Schizophrenia, Sialyltransferases, Cohort Studies, Gene Expression Regulation, Enzymologic, Case-Control Studies, Prefrontal Cortex, Mood Disorders, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci
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