Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26
Identification of Sialyltransferase 8B as a Generalized Susceptibility Gene for Psychotic and Mood Disorders on Chromosome 15q25-26
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唾液酸转移酶 8B 鉴定为染色体 15q25-26 上精神病和情绪障碍的普遍易感基因
作者：
E. McAuley;A. Scimone;Y. Tiwari;Giti Agahi;B. Mowry;E. Holliday;J. Donald;C. Weickert;P. Mitchell;P. Schofield;Janice M. Fullerton
我们先前使用35个具有广泛临床表型的大家族，包括双相情感障碍（I型和II型），复发性单相抑郁症和双相情感障碍，在15 q25 -26上确定了一个显著的双相谱系障碍连锁峰。然而，尚未鉴定出促成该信号的特定基因。通过在澳大利亚病例对照队列（n = 385）中进行的精细映射关联研究，我们发现唾液酸转移酶8B（ST 8 SIA 2）基因编码一种酶，该酶使参与神经元可塑性的蛋白质糖基化，该酶先前已显示与精神分裂症和自闭症相关，与双相谱系障碍的风险增加相关。 在ST 8 SIA 2中观察到与SNP的名义单点关联（rs 4586379，P = 0.0043; rs 2168351，P = 0.0045），并且鉴定了特定风险单倍型（频率：双相vs对照= 0.41 vs 0.31; χ2 = 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（χ2 = 8.41，P = 0.004，OR = 1.82）。 使用来自NIMH双相情感障碍（n = 2055）和NIMH精神分裂症（n = 2550）队列的GWAS数据，等效单倍型在双相情感障碍中显著过代表（χ2 = 5.91，P = 0.015，OR = 1.29），在精神分裂症中具有相同的作用方向，尽管不显著（χ2 = 2.3，P = 0.129，OR = 1.09）。 我们证明了ST 8 SIA 2基因表达在人脑发育过程中的显著下调，并显示出对成人皮质中ST 8 SIA 2 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，ST 8 SIA 2基因的变异与精神疾病风险增加有关，限制了神经元的可塑性，破坏了早期神经元网络的形成，使发育中的和成年的大脑更容易受到二次遗传或环境的伤害。
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; χ2 = 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) (χ2 = 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 (χ2 = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ2 = 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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DOI：
10.1176/appi.ajp.2010.10091340
发表时间：
2011-03
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Gershon ES;Alliey-Rodriguez N;Liu C
通讯作者：
Liu C
影响因子：
9.8
作者：
Hodgkinson, CA;Goldman, D;Malhotra, AK
通讯作者：
Malhotra, AK
影响因子：
9.8
作者：
Holmans, P;Zubenko, GS;Levinson, DF
通讯作者：
Levinson, DF
影响因子：
9.8
作者：
Hattori, E;Liu, CY;Gershon, ES
通讯作者：
Gershon, ES