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. 2012;7(5):e38172.
doi: 10.1371/journal.pone.0038172. Epub 2012 May 31.

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26

Erica Z McAuley  1 , Anna Scimone, Yash Tiwari, Giti Agahi, Bryan J Mowry, Elizabeth G Holliday, Jennifer A Donald, Cynthia Shannon Weickert, Phillip B Mitchell, Peter R Schofield, Janice M Fullerton
Affiliations

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26

Erica Z McAuley et al. PLoS One. 2012.

Abstract

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Association analysis and gene map of 6.5 Mb candidate locus.
−Log of the P values of genotyped SNPs are represented on the y-axis with chromosome position in kilobases on the x-axis. The red diamonds indicate the P values less than 0.05. The relative positions of protein coding genes in the locus are shown above.
Figure 2
Figure 2. Multidimensional scaling of GAIN data showing no evidence of population stratification.
A) bipolar disorder case control cohort; B) schizophrenia case control cohort. Cases and controls are represented by the red and blue crosses respectively.
Figure 3
Figure 3. Linkage disequilibrium structure of the ST8SIA2 and C15ORF32 region, spanning 132 kb, in Caucasian Europeans from the CEPH collection.
LD blocks are indicated in black triangles, with red shading indicating high LD (D′) for CEU genotypes downloaded from HAPMAP3 (release #28; 90720–90845 kb, NCBI build 36.1). Locations of SNPs which make up the risk haplotype in the Australian bipolar disorder cohort are indicated by the black asterisks. Affymetrix SNPs used to replicate the haplotype association in the NIMH bipolar and schizophrenia case-control samples are indicated by the red asterisks. Insets A–C show the relationships between common haplotypes (frequency greater than 2%) in the CEPH genotype data using different SNP combinations. Haplotypes indicated by the superscript letters in inset A (when both NIMH and Australian SNPs are considered simultaneously) indicate those haplotypes which are indistinguishable when using only the Australian SNPs (inset B), or the surrogate NIMH SNPs (inset C). The strongly associated SNPs from genome wide association studies of bipolar disorder in the Han Chinese (rs8040009) , and of autism in Caucasians (rs3784730) are indicated by the blue and green asterisks respectively.
Figure 4
Figure 4. The mean normalized quantity for each developmental group.
The age range in years and number of subjects per group (n) were: neonate 0.11–0.24 (n = 10); infant 0.32–0.91 (n = 13); toddler 1.58–4.86 (n = 9); school age 6.88–12.97 (n = 8); teenage 15–17.82 (n = 8); young adult 20.14–25.38 (n = 8); adult 35.99–48.69 (n = 7). Error bars indicate one standard deviation from the mean. Significant group differences from post-hoc Fisher LSD tests comparing neonates to the six other developmental age groups are indicated, where one asterisk represents P<0.001, two asterisks represent P<0.0001 and three asterisks represent P<0.00001.
Figure 5
Figure 5. The effect of protective haplotype on ST8SIA2 gene expression in adult post-mortem DLPFC.
Normalised and transformed ST8SIA2 expression was regressed against age, and standardized residuals were used to compare the effect of haplotype in Caucasian brains from the Stanley Medical Research Institute Array cohort. The mean values for each group are represented by horizontal black bars, and boxes represent the 95% confidence intervals of each group (± standard errors), with the numbers of individuals in each group indicated within the boxes. One individual homozygous for the protective haplotype was identified, and was included in the ≥1 copy group. There was no significant overall effect of diagnosis on expression (three-way ANOVA: F(2, 94) = 0.486, p = 0.617), but a trend towards lower ST8SIA2 expression in schizophrenia cases compared to controls (ANOVA: F(1, 61) = 2.737, p = 0.103; combined diagnostic group ANOVA: F(1, 91) = 1.948, p = 0.166). Significant diagnosis×haplotype effects were observed for the protective haplotype in control versus the combined diagnostic group (ANOVA: F(1, 87) = 6.031, p = 0.016). Post-hoc comparisons showed significant reductions in ST8SIA2 expression in non-haplotype carriers in cases compared to non-haplotype carrier controls (Fisher LSD: combined diagnoses p = 0.007, indicated by double asterisk), as well as control carriers versus control non-carriers (Fisher LSD: p = 0.034, indicated by single asterisk).
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