Psychiatric Genetics, Neuroscience Research Australia, Sydney, New South Wales, Australia.
PLoS One. 2012;7(5):e38172. doi: 10.1371/journal.pone.0038172. Epub 2012 May 31.
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.
我们先前利用包含双相障碍（I 型和 II 型）、复发性单相抑郁和分裂情感障碍在内的广泛临床表型的 35 个扩展家系，在 15q25-26 区鉴定到一个显著的双相障碍谱障碍连锁峰。然而，导致这一信号的特定基因尚未被确定。通过在澳大利亚病例对照队列（n=385）中的精细定位关联研究，我们发现唾液酸转移酶 8B（ST8SIA2）基因与双相障碍谱障碍的风险增加相关，该基因编码一种使参与神经元可塑性的蛋白质发生糖基化的酶，该基因先前与精神分裂症和自闭症均有关联。在 ST8SIA2 基因中观察到单点关联（rs4586379，P=0.0043；rs2168351，P=0.0045），并鉴定到一个特定的风险单倍型（频率：双相障碍比对照组=0.41 比 0.31；χ(2)=6.46，P=0.011，OR=1.47）。在澳大利亚精神分裂症病例对照队列（n=256）中也观察到特定风险单倍型的过度表达（χ(2)=8.41，P=0.004，OR=1.82）。利用 NIMH 双相障碍（n=2055）和 NIMH 精神分裂症（n=2550）队列的 GWAS 数据，在双相障碍中，等效单倍型显著过度表达（χ(2)=5.91，P=0.015，OR=1.29），在精神分裂症中也有相同的效应方向，但不显著（χ(2)=2.3，P=0.129，OR=1.09）。我们证明了 ST8SIA2 基因在人类大脑发育过程中的显著下调，并在成人皮质中观察到 ST8SIA2 mRNA 水平的显著单倍型×诊断效应（ANOVA：F(1,87)=6.031，P=0.016）。这些发现表明，ST8SIA2 基因的变异与精神疾病风险增加相关，其作用是限制神经元可塑性并破坏早期神经元网络形成，使发育中的和成年期的大脑更容易受到二次遗传或环境损伤。
