Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes
Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes
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DOI：
10.1016/j.cels.2017.02.009
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发表时间：
2017-04-26
期刊：
影响因子：
9.3
通讯作者：
Abeliovich, Asa
中科院分区：
文献类型：
--
作者：
Rhinn, Herve;Abeliovich, Asa
人类与年龄相关的特征，如认知能力下降，在人群中可能会有很大的差异，有些人表现出的特征在给定的实际年龄是预料不到的。在这里，我们提出了差异衰老（D-aging），这是一种无偏的方法，可以量化感兴趣组织中年龄相关表型的个体变异性，并将这种方法应用于分析来自几个队列共1904个尸检人脑样本的现有转录组全脑皮层基因表达数据。随后，我们进行了一项全基因组关联研究，发现TMEM106B和GRN基因位点是大脑皮层d老化的决定因素，具有全基因组意义，之前与额颞叶痴呆相关。即使在没有已知脑部疾病的情况下，TMEM106B风险变异也与炎症、神经元丧失和认知缺陷有关，而且它们对老年人（50 - 65岁）大脑额叶皮层的影响具有高度选择性。我们所描述的方法框架可以广泛应用于与老化或其他参数相关的数量性状的分析。
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 (D-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 D-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.