Department of Neurology, Philipps-Universität, Marburg, Germany.
Nat Genet. 2011 Jun 19;43(7):699-705. doi: 10.1038/ng.859.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.
进行性核上性麻痹（PSP）是一种以 tau 神经病理学为特征的运动障碍。tau 异常沉积的脑部疾病称为 tau 病，最常见的是阿尔茨海默病。tau 病的环境病因包括与某些运动相关的反复头部创伤。为了确定导致 tau 病风险的常见遗传变异，我们对 1114 名 PSP 患者（病例）和 3247 名对照者（第 1 阶段）进行了全基因组关联研究，然后在第 2 阶段对 1051 名病例和 3560 名对照者进行基因分型，以检测在第 1 阶段产生 P ≤ 10(-3)的 SNP。我们发现了与 PSP 风险相关的以前未识别的显著信号（P < 5×10(-8)），这些信号与 STX6、EIF2AK3 和 MOBP 相关。我们证实了 MAPT 中影响 PSP 风险的两个独立变异，其中一个影响 MAPT 脑表达。所涉及的基因编码在高尔基体内体界面处进行囊泡-膜融合的蛋白、内质网未折叠蛋白反应的蛋白和髓鞘结构成分的蛋白。
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