Study Report

Comment on Study

View All Comments on Study

Basic Info

Reference	McAuley, E. Z., 2012 PMID: 22693595
Citation	McAuley, E. Z., A. Scimone, et al. (2012). "Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26." PLoS One 7(5): e38172.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	219 cases and 166 controls in bipolar disorder case control cohort, 310 cases and 128 controls in the Schizophrenia cohort
SNP/Region/Marker Size	349 SNPs
Predominant Ethnicity	Caucasian
Population	Australian and American
Gender	50% were female of Australian Bipolar disorder cohort, 85 men and 43 women cases in the Australian Schizophrenia cohort
Age Group	adults : average age of cases=46.7 (SD=15.3), average age of controls=60.3 (SD=13.5) for bipolar disorder case control cohort

Detail Info

Sample Diagnosis	Research Diagnostic Criteria (RDC) for Australian Bipolar disorder cohort, DSM-III-R for Australian Schizophrenia cohort, DSM-IV or ICD-10 for NIMH bipolar disorder and schizophrenia cohorts
Sample Status	Australian Bipolar disorder cohort: The Australian bipolar disorder case-control cohort was mostly selected from families previously used for linkage analysis and was recruited through the Mood Disorders Unit and Black Dog Institute, Prince of Wales Hospital/School of Psychiatry, University of New South Wales, Australia. In total, 50.5% of the sample had psychotic features, 70% had a family history of bipolar disorder, and 87% had a family history of bipolar disorder or depression. Bipolar I disorder (BPI: n=158), Bipolar II disorder (BPII: n=41), Schizoaffective Disorder-Manic type (SZ/MA: n=10), Major Depressive Disorder (MDD: n=10). Australian Schizophrenia cohort: Samples were selected from a larger cohort (n=310), initially recruited for the Australian national prevalence study of psychosis, for which diagnoses were assigned using the Diagnostic Interview for Psychosis. NIMH bipolar disorder and schizophrenia cohorts: Genome wide association study data was downloaded from the Genetic Association Information Network (GAIN) through the US based National Institutes of Health.
Replication Size	1034 controls and 1021 patients with bipolar disorder, 1378 controls and 1172 cases with schizophrenia from NIMH
Technique	genotyping
Statistical Method	Statistical analyses were performed with PLINK v1.02 software. SNPs failing the Hardy-Weinberg exact test at a 0.001 significance threshold were removed. To devise empirical P values for SNP and haplotype association, ten thousand permutations for each SNP were performed using the -mperm option. Multimarker haplotype analysis was conducted using probabilistically inferred haplotypes for each individual, generated using a standard E-M algorithm in PLINK. Haplotype association analysis was performed using the -hap-assoc option with a sliding windows (-hap-window 3) or specified haplotype (-hap-snps) approach with standard association testing. Conditional regression-based association using the -chap option was performed on specific haplotypes of interest.
Result Summary	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; chi(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) (chi(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 (chi(2) = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (chi(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 haplotypexdiagnosis 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.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 18)

SNP	Related Gene(s)	Allele Change	Statistical Values	Author Comments	Result Category
rs11637898	ST8SIA2	A/G	P-value = 0.048, Empirical P-value = 0.064, OR (95% CI)=0.75 (0.56-0.99) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. More...	Positive
rs11074070	ST8SIA2 ENO1P2	C/A	P-value = 0.036, Empirical P-value = 0.04, OR (95% CI)=0.73 (0.55-0.98) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs13380006	ST8SIA2 C15orf32	A/G	P-value = 0.034, Empirical P-value = 0.042, OR (95% CI)=1.41 (0.97-1.82) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs12441404	ST8SIA2 C15orf32	A/G	P-value = 0.034, Empirical P-value = 0.042, OR (95% CI)=1.41 (0.97-1.82) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs2035645	ST8SIA2	A/C	P-value = 0.042, Empirical P-value = 0.06, OR (95% CI)=1.36 (1.00-1.78) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. More...	Positive
rs1455773	ST8SIA2 C15orf32	A/G	P-value = 0.026, Empirical P-value = 0.031, OR (95% CI)=1.44 (0.99-1.86) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs2280468	ACAN	A/G	P-value = 0.031, Empirical P-value = 0.03, OR (95% CI)=0.70 (0.51-0.96) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs2168351	ST8SIA2	G/A	P-value = 0.005, Empirical P-value = 0.007, OR (95% CI)=0.65 (0.49-0.89) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs3858917	ST8SIA2	C/A	P-value = 0.046, Empirical P-value = 0.055, OR (95% CI)=0.74 (0.56-0.99) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. More...	Positive
rs3784735	ST8SIA2	C/A	P-value = 0.032, Empirical P-value = 0.034, OR (95% CI)=0.73 (0.54-0.97) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs4777760	RGMA	A/G	P-value = 0.042, Empirical P-value = 0.045, OR (95% CI)=0.74 (0.58-1.03) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs4586379	ST8SIA2	G/A	P-value = 0.004, Empirical P-value = 0.006, OR (95% CI)=0.61 (0.43-0.85) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs6496898	SLCO3A1	G/A	P-value = 0.033, Empirical P-value = 0.035, OR (95% CI)=1.43 (1.04-1.99) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs4777974	ST8SIA2	G/A	P-value = 0.041, Empirical P-value = 0.05, OR (95% CI)=1.36 (1.00-1.79) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. More...	Positive
rs7174649		A/G	P-value = 0.026, Empirical P-value = 0.035, OR (95% CI)=0.63 (0.42-0.94) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs7169541		G/C	P-value = 0.045, Empirical P-value = 0.045, OR (95% CI)=0.74 (0.55-0.99) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs871167	SLCO3A1	A/G	P-value = 0.034, Empirical P-value = 0.046, OR (95% CI)=1.39 (1.06-1.93) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive
rs7175812	SLCO3A1	G/A	P-value = 0.036, Empirical P-value = 0.035, OR (95% CI)=1.53 (1.07-2.38) in the Australian bipolar disorder cohort	Nominally significant association (P < 0.05) was found with ...... Nominally significant association (P < 0.05) was found with 18 SNPs. Association with 14 of these SNPs held true when empirical P values were obtained through 10, 000 replicate permutations. More...	Positive

Haplotypes reported by this study for BD (count: 4)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs4586379 - rs8025225 - rs11074066 - rs11074067 - rs2035645	T-T-A-G-T	ST8SIA2	P-value = 0.015, X<sup>2</sup>=5.91, OR (95% CI)=1.29 (1.03-1.33) in NIMH BP	The most common haplotype (TTAGT, equivalent to the risk hap...... The most common haplotype (TTAGT, equivalent to the risk haplotype identified in the Australian cohort) was significantly over represented in the NIMH bipolar disorder cases compared to controls. More...	Positive
rs4586379 - rs2035645 - rs4777974 - rs11637898 - rs11074070 - rs3784735	G-C-A-A-C-C	ST8SIA2	P-value = 0.015, X<sup>2</sup>=5.97, OR (95% CI)=0.5857 (0.38-0.90) in Aus BP	GCAACC representing the third most common haplotype had a hi...... GCAACC representing the third most common haplotype had a higher frequency in controls than in cases, constituted a putative protective haplotype. More...	Positive
rs4586379 - rs2035645 - rs4777974 - rs11637898 - rs11074070 - rs3784735	A-A-G-G-A-A	ST8SIA2	P-value = 0.011, X<sup>2</sup>=6.46, OR (95% CI)=1.473 (1.09-1.99) in Aus BP	Global significant association across a 6 SNP haplotype span...... Global significant association across a 6 SNP haplotype spanning 54 kb, starting 16 kb upstream of ST8SIA2 through to the middle of intron 2, was found with SNPs rs4586379, rs2035645, rs4777974, rs11637898, rs11074070 and rs3784735. The most common haplotype AAGGAA, had a higher frequency in cases than in controls constituted a putative bipolar risk haplotype. More...	Positive
rs4586379 - rs8025225 - rs11074066 - rs11074067 - rs2035645	C-C-C-C-G	ST8SIA2	P-value = 0.09, X<sup>2</sup>=2.83, OR (95% CI)=0.87 (0.73-1.02) in NIMH BP	No significant association was reported in this study. No significant association was reported in this study.	Negative

Genes reported by this study for BD (count: 5)

Gene	Statistical Values/Author Comments	Result Category
ST8SIA2	These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental i...... 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. More...	Positive
C15orf32	Nominally significant association (P < 0.05) was found with 3 SNPs with BD. Nominally significant association (P < 0.05) was found with 3 SNPs with BD.	Positive
ACAN	Nominally significant association (P < 0.05) was found with 1 SNP with BD. Nominally significant association (P < 0.05) was found with 1 SNP with BD.	Positive
RGMA	Nominally significant association (P < 0.05) was found with 1 SNP with BD. Nominally significant association (P < 0.05) was found with 1 SNP with BD.	Positive
SLCO3A1	Nominally significant association (P < 0.05) was found with 3 SNPs with BD. Nominally significant association (P < 0.05) was found with 3 SNPs with BD.	Positive

Genetic factors reported by this study for SZ and/or MDD

SNPs reported by this study for SZ/MDD

Disease	SNP	Related Gene(s)	Statistical Values	Description	Result Category
SZ	rs11074070	ST8SIA2 ENO1P2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs1455773	ST8SIA2 C15orf32	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs13380006	ST8SIA2 C15orf32	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs12441404	ST8SIA2 C15orf32	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs11637898	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs3784735	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs2280468	ACAN	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs2168351	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs2035645	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs3858917	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs4586379	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs4777760	RGMA	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs4777974	ST8SIA2	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs6496898	SLCO3A1	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs7169541		P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs7174649		P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs7175812	SLCO3A1	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative
SZ	rs871167	SLCO3A1	P-value > 0.075	Single SNP analysis did not yield significant evidence for association.	Negative

Haplotypes reported by this study for SZ/MDD

Disease	Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Description	Result Category
SZ	rs4586379 - rs8025225 - rs11074066 - rs11074067 - rs2035645	C-C-C-C-G	ST8SIA2	P-value = 0.408, X<sup>2</sup>=0.68, OR (95% CI)=0.938 (0.81-1.09) in NIMH SZ	No significant association was reported in this study.	Negative
SZ	rs4586379 - rs8025225 - rs11074066 - rs11074067 - rs2035645	T-T-A-G-T	ST8SIA2	P-value = 0.129, X<sup>2</sup>=2.30, OR (95% CI)=1.09 (0.97-1.23) in NIMH SZ	This haplotype also showed the same direction of effect in the NIMH cases with schizophrenia compared to controls, although it did not reach statistical significance.	Negative
SZ	rs4586379 - rs2035645 - rs4777974 - rs11637898 - rs11074070 - rs3784735	G-C-A-A-C-C	ST8SIA2	P-value = 0.021, X<sup>2</sup>=5.30, OR (95% CI)=0.515 (0.29-0.92) in Aus SZ	the protective haplotype was over-represented in controls on conditional haplotype analysis	Positive
SZ	rs4586379 - rs2035645 - rs4777974 - rs11637898 - rs11074070 - rs3784735	A-A-G-G-A-A	ST8SIA2	P-value = 0.004, X<sup>2</sup>=8.41, OR (95% CI)=1.82 (1.2-2.74) in Aus SZ	We found that the specific AAGGAA risk haplotype was significantly over-represented in schizophrenia cases compared to controls when a conditional analysis was performed.	Positive

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	SLCO3A1	No significant association was reported in this study.	Negative
SZ	ST8SIA2	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.	Positive
SZ	ACAN	No significant association was reported in this study.	Negative
SZ	RGMA	No significant association was reported in this study.	Negative
SZ	C15orf32	No significant association was reported in this study.	Negative