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.