Neuroscience Research Australia, Randwick, Sydney, NSW, Australia.
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Transl Psychiatry. 2018 Jan 22;8(1):21. doi: 10.1038/s41398-017-0052-z.
Brain white matter abnormalities are evident in individuals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of individuals with schizophrenia (n = 281) and healthy controls (n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype (p < 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.
脑白质异常在精神分裂症患者及其一级亲属中都很明显，这表明某些改变可能与潜在的遗传风险有关。ST8 唾液酸转移酶 2（ST8SIA2）基因编码α-2,8-唾液酸转移酶 8B 酶，有助于神经元迁移和突触可塑性，先前被认为是精神分裂症易感基因。本研究使用扩散加权成像技术，对来自五个澳大利亚研究地点的精神分裂症患者（n=281）和健康对照者（n=172），研究了 ST8SIA2 中特定单倍型对脑白质微观结构的影响程度。采用基于簇的统计学方法，对所有脑白质体素进行了诊断状态与单倍型拷贝数（0 或≥1）之间的相互作用检验。右侧顶叶的各向异性分数（FA）显示诊断和 ST8SIA2 保护性单倍型之间存在显著的相互作用（p<0.05，经家族错误率（FWER）校正的簇）。保护性单倍型与对照组 FA 增加有关，但在精神分裂症患者中，这种效应相反。白质纤维追踪显示，感兴趣区被上纵束、辐射冠和内囊后肢的部分纤维穿过。事后分析表明，该区域交界处 FA 降低与精神分裂症患者的智商降低有关。ST8SIA2 风险单倍型拷贝数对白质没有任何差异影响。本研究为常见疾病相关单倍型与白质微观结构的特定变化之间提供了联系，这可能与精神疾病的弹性或风险有关，为 ST8SIA2 参与精神分裂症的病理生理学提供了进一步的有力证据。
