Centre for Studies on the Prevention of Alzheimer's Disease, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Centre for Studies on the Prevention of Alzheimer's Disease, Douglas Mental Health University Institute, Montreal, Quebec, Canada.
Neurobiol Aging. 2018 Jun;66:180.e1-180.e9. doi: 10.1016/j.neurobiolaging.2018.01.018. Epub 2018 Feb 9.
Genome-wide association studies have identified several cholesterol metabolism-related genes as top risk factors for late-onset Alzheimer's disease (LOAD). We hypothesized that specific genetic variants could act as disease-modifying factors by altering the expression of those genes. Targeted association studies were conducted with available genomic, transcriptomic, proteomic, and histopathological data from 3 independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Quebec Founder Population (QFP), and the United Kingdom Brain Expression Consortium (UKBEC). First, a total of 273 polymorphisms located in 17 cholesterol metabolism-related loci were screened for associations with cerebrospinal fluid LOAD biomarkers beta amyloid, phosphorylated tau, and tau (from the ADNI) and with amyloid plaque and tangle densities (from the QFP). Top polymorphisms were then contrasted with gene expression levels measured in 134 autopsied healthy brains (from the UKBEC). In the end, only SREBF2 polymorphism rs2269657 showed significant dual associations with LOAD pathological biomarkers and gene expression levels. Furthermore, SREBF2 expression levels measured in LOAD frontal cortices inversely correlated with age at death; suggesting a possible influence on survival rate.
全基因组关联研究已经确定了几个胆固醇代谢相关基因是晚发性阿尔茨海默病（LOAD）的顶级风险因素。我们假设特定的遗传变异可以通过改变这些基因的表达来充当疾病修饰因子。使用来自 3 个独立队列的现有基因组、转录组、蛋白质组和组织病理学数据进行了靶向关联研究：阿尔茨海默病神经影像学倡议（ADNI）、魁北克创始人群体（QFP）和英国大脑表达联盟（UKBEC）。首先，筛选了位于 17 个胆固醇代谢相关基因座中的 273 个多态性，以与脑脊液 LOAD 生物标志物β淀粉样蛋白、磷酸化 tau 和 tau（来自 ADNI）以及淀粉样斑块和缠结密度（来自 QFP）相关联。然后，将顶级多态性与在 134 例尸检健康大脑中测量的基因表达水平进行对比（来自 UKBEC）。最后，只有 SREBF2 多态性 rs2269657 显示出与 LOAD 病理生物标志物和基因表达水平的双重显著关联。此外，在 LOAD 额叶皮质中测量的 SREBF2 表达水平与死亡年龄呈负相关；表明可能对存活率有影响。
