Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26

University of Illinois at Chicago, United States of America
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e38172. DOI: 10.1371/journal.pone.0038172
Source: PubMed


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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Available from: Philip Bowden Mitchell
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    • "This rare haplotype is present in the patient's mother, along with the most common haplotype (freq ¼ 0.723). Neither of these maternal haplotypes are represented by the risk or protective haplotypes previously reported to be associated with bipolar disorder and schizophrenia [McAuley et al., 2012]. The rarity of the remaining haplotype in the patient suggests the deletion event may have arisen on the paternal chromosome, either through direct inheritance or a de novo mutational event, although DNA from the father would be required to confirm this. "

    Full-text · Article · Apr 2015 · American Journal of Medical Genetics Part A
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    • "In summary, our study demonstrates that polySia is essential for cortical interneuron development and provides a possible link between neurodevelopmental deficits and the emerging evidence that genetic variation of the polySia-NCAM system may be associated with schizophrenia (Arai et al., 2006; Tao et al., 2007; Brennaman and Maness, 2010; McAuley et al., 2012). Reporter assays with a risk haplotype for ST8SIA2 suggested higher expression (Arai et al., 2006), whereas another risk variant is associated with lower ST8SIA2 mRNA levels in post-mortem PFC samples (McAuley et al., 2012). "
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    ABSTRACT: Polysialic acid (polySia) is a unique glycan modification of the neural cell adhesion molecule NCAM and a major determinant of brain development. Polysialylation of NCAM is implemented by the two polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4. Dysregulation of the polySia-NCAM system and variation in ST8SIA2 has been linked to schizophrenia and other psychiatric disorders. Here, we show reduced interneuron densities in the medial prefrontal cortex (mPFC) of mice with either partial or complete loss of polySia synthesizing capacity by ablation of St8sia2, St8sia4, or both. Cells positive for parvalbumin and perineuronal nets as well as somatostatin-positive cells were reduced in the mPFC of all polyST-deficient lines, whereas calretinin-positive cells and the parvalbumin-negative fraction of calbindin-positive cells were unaffected. Reduced interneuron numbers were corroborated by analyzing polyST-deficient GAD67-GFP knock-in mice. The accumulation of precursors in the ganglionic eminences and reduced numbers of tangentially migrating interneurons in the pallium were observed in polyST-deficient embryos. Removal of polySia by endosialidase treatment of organotypic slice cultures led to decreased entry of GAD67-GFP-positive interneurons from the ganglionic eminences into the pallium. Moreover, the acute loss of polySia caused significant reductions in interneuron velocity and leading process length. Thus, attenuation of polySia interferes with the developmental migration of cortical interneurons and causes pathological changes in specific interneuron subtypes. This provides a possible link between genetic variation in polyST genes, neurodevelopmental alterations and interneuron dysfunction in neuropsychiatric disease.
    Preview · Article · Jul 2014 · Development
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    • "Recently, a relationship between SNPs in the promoter region of the ST8SIA2 gene and schizophrenia was identified by genome-wide association studies in the Japanese (Arai et al., 2006) and Chinese Han populations (Tao et al., 2007). The ST8SIA2 gene is also reported to be a generalized susceptibility marker for psychotic and mood disorders on chromosome 15q25-26 (McAuley et al., 2012), and is associated with an increased risk of mental illness, such as autism (Anney et al., 2010). Interestingly, the mutation of synCAM, which is another substrate for ST8SIA2, is also related with autism spectrum disorders (Zhiling et al., 2008). "
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    ABSTRACT: Psychiatric disorders are a group of human diseases that impair higher cognitive functions. Whole-genomic analyses have recently identified susceptibility genes for several psychiatric disorders, including schizophrenia. Among the genes reported to be involved in psychiatric disorders, a gene encoding a polysialyltransferase involved in the biosynthesis of polysialic acid (polySia or PSA) on cell surfaces has attracted attention for its potential role in emotion, learning, memory, circadian rhythm, and behaviors. PolySia is a unique polymer that spatio-temporally modifies neural cell adhesion molecule (NCAM) and is predominantly found in embryonic brains, although it persists in areas of the adult brain where neural plasticity, remodeling of neural connections, or neural generation is ongoing, such as the hippocampus, subventricular zone (SVZ), thalamus, prefrontal cortex, and amygdala. PolySia is thought to be involved in the regulation of cell-cell interactions; however, recent evidence suggests that it is also involved in the functional regulation of ion channels and neurologically active molecules, such as Brain-derived neurotrophic factor (BDNF), FGF2, and dopamine (DA) that are deeply involved in psychiatric disorders. In this review, the possible involvement of polysialyltransferase (ST8SIA2/ST8SiaII/STX/Siat8B) and its enzymatic product, polySia, in schizophrenia is discussed.
    Full-text · Article · May 2013 · Frontiers in Cellular Neuroscience
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