Departments of Pathology, Cell Biology, and Neurology, Columbia University, New York, NY 10032, USA; Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
Cell Syst. 2017 Apr 26;4(4):404-415.e5. doi: 10.1016/j.cels.2017.02.009. Epub 2017 Mar 18.
Human age-associated traits, such as cognitive decline, can be highly variable across the population, with some individuals exhibiting traits that are not expected at a given chronological age. Here we present differential aging (Δ-aging), an unbiased method that quantifies individual variability in age-associated phenotypes within a tissue of interest, and apply this approach to the analysis of existing transcriptome-wide cerebral cortex gene expression data from several cohorts totaling 1,904 autopsied human brain samples. We subsequently performed a genome-wide association study and identified the TMEM106B and GRN gene loci, previously associated with frontotemporal dementia, as determinants of Δ-aging in the cerebral cortex with genome-wide significance. TMEM106B risk variants are associated with inflammation, neuronal loss, and cognitive deficits, even in the absence of known brain disease, and their impact is highly selective for the frontal cerebral cortex of older individuals (>65 years). The methodological framework we describe can be broadly applied to the analysis of quantitative traits associated with aging or with other parameters.
人类与年龄相关的特征，如认知能力下降，在人群中可能存在高度的可变性，有些个体表现出的特征与给定的实际年龄不符。在这里，我们提出了差异老化（Δ-aging），这是一种定量分析特定组织中与年龄相关表型个体差异的无偏方法，并将其应用于对来自多个队列的总计 1904 个人脑样本的现有全转录组大脑皮层基因表达数据的分析。随后，我们进行了全基因组关联研究，确定了先前与额颞叶痴呆相关的 TMEM106B 和 GRN 基因座，作为大脑皮层 Δ-aging 的全基因组显著决定因素。TMEM106B 风险变异与炎症、神经元丧失和认知缺陷有关，即使在没有已知脑部疾病的情况下也是如此，而且其影响对年龄较大的个体（>65 岁）的额叶大脑皮层具有高度选择性。我们描述的方法框架可以广泛应用于与衰老或其他参数相关的定量特征的分析。
