GWAS 分析脑脊液 tau 水平鉴定阿尔茨海默病的风险变异。
GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.
机构信息
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
出版信息
Neuron. 2013 Apr 24;78(2):256-68. doi: 10.1016/j.neuron.2013.02.026. Epub 2013 Apr 4.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
脑脊液（CSF）tau、磷酸化苏氨酸 181 位的 tau（ptau）和 Aβ₄₂ 是阿尔茨海默病（AD）的既定生物标志物，已被用作遗传分析的定量特征。我们进行了迄今为止发表的脑脊液（CSF）tau/ptau 水平的最大全基因组关联研究（n = 1,269），确定了三个与 CSF tau 和 ptau 水平全基因组显著相关的位点：rs9877502（tau 的 p 值为 4.89×10⁻⁹）位于 3q28 之间 GEMC1 和 OSTN 之间，rs514716（tau 和 ptau 的 p 值分别为 1.07×10⁻⁸和 3.22×10⁻⁹）位于 9p24.2 内 GLIS3 内，rs6922617（CSF ptau 的 p 值为 3.58×10⁻⁸）位于 6p21.1 内 TREM 基因簇内，该区域最近报道存在增加 AD 风险的罕见变异。在独立的数据集中，rs9877502 与 AD 风险、缠结病理和整体认知下降均具有很强的相关性（p = 2.67×10⁻⁴，0.039，4.86×10⁻⁵，分别），说明这种基于表型的方法如何用于识别新的 AD 风险位点。
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