全基因组关联分析揭示了脑脊液中人类 Aβ42 和 τ 蛋白水平的遗传效应：一项病例对照研究。
Genome-wide association reveals genetic effects on human Aβ42 and τ protein levels in cerebrospinal fluids: a case control study.
机构信息
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
出版信息
BMC Neurol. 2010 Oct 8;10:90. doi: 10.1186/1471-2377-10-90.
BACKGROUND
Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ1-42, T-tau, and P-tau181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.
METHODS
Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ1-42, T-tau, and P-tau181P Levels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.
RESULTS
We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ1-42 levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. CYP19A1 'aromatase' (rs2899472), NCAM2, and multiple SNPs located on chromosome 10 near the ARL5B gene demonstrated the strongest associations with Aβ1-42 in normal subjects. Two genes found to be near the top SNPs, CYP19A1 (rs2899472, p = 1.90 × 10(-7)) and NCAM2 (rs1022442, p = 2.75 × 10(-7)) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau181P levels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ1-42).
CONCLUSIONS
Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.
背景
阿尔茨海默病（AD）是一种常见的、高度遗传性疾病，许多基因和基因变异与 AD 有关，包括 APOE ε2/ε3/ε4。然而，正常认知、轻度认知障碍（MCI）和 AD 患者脑脊液（CSF）中 Aβ1-42、T-tau 和 P-tau181P 水平变化的遗传背景尚不清楚。我们进行了全基因组关联研究（GWAS），以便更好地定义与 CSF 水平相关的这三种状态的遗传背景。
方法
研究对象为阿尔茨海默病神经影像学倡议（ADNI）的参与者。GWAS 数据集由 818 名参与者组成（主要为白种人），使用 Illumina Human Genome 610 Quad BeadChips 进行基因分型。该样本包括 410 名受试者（119 名正常、115 名 MCI 和 176 名 AD），测量了 CSF Aβ1-42、T-tau 和 P-tau181P 水平。我们使用 PLINK 寻找与三种 CSF 生物标志物水平相关的遗传关联。使用加性、显性和一般关联模型测试了每个基因座的 498,205 个 SNP 的关联，同时考虑了 APOE 基因型和年龄。最后，使用 ALIGATOR 软件努力更好地识别相关的生化途径。
结果
我们发现，尽管每个亚组的 CSF 水平基本相同，但 APOE 基因型与 CSF 水平存在一些关联；对于每个亚组，APOE 基因剂量的增加与 CSF Aβ1-42 水平降低有关。与正常组相比，AD 患者的 T-tau 水平往往较高。从调整了 APOE 基因型和年龄作为协变量后的结果来看，AD 患者的 CSF 水平与任何 SNP 均无关联。CYP19A1 '芳香酶'（rs2899472）、NCAM2 和位于染色体 10 上接近 ARL5B 基因的多个 SNP 与正常组中的 Aβ1-42 显示出最强的关联。在最接近 top SNPs 的两个基因中，CYP19A1（rs2899472，p=1.90×10(-7)) 和 NCAM2（rs1022442，p=2.75×10(-7)) 已被报道为与 AD 进展相关的遗传因素。在 AD 患者中，APOE ε2/ε3 和 ε2/ε4 基因型与 T-tau 水平升高有关，而 ε4/ε4 基因型与 T-tau 和 P-tau181P 水平升高有关。通路分析检测到几个与正常 CSF β-淀粉样肽（Aβ1-42）相关的生物学途径。
结论
我们的全基因组关联分析确定了几个作为 CSF 生物标志物重要因素的 SNP。我们还通过通路分析提供了额外候选遗传风险因素的新证据，这些因素可以在进一步的研究中进行检验。
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