Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

译文

认知能力下降是变老的一个令人恐惧的方面。这是导致老年生活质量下降和失去独立性的主要原因。我们调查了五个老年人群对非病理性认知衰老个体差异的遗传贡献。在英格兰和苏格兰的认知老化遗传学 (CAGES) 项目中,我们使用549   692单核苷酸多态性 (snp) 对3511无关的成年人进行了全基因组关联分析。这些个体具有详细的纵向认知数据,从中构建了用于测量每个人的认知变化的表型。位于tom40 (线粒体外膜40同源物的转位酶) 中的一个SNP-rs2075650与认知老化具有全基因组显着关联 (P = 2.5 × 10(-8))。该结果在三个独立的瑞典队列的荟萃分析中被复制 (P = 2.41 × 10(-6))。先前与认知衰老相关的载脂蛋白E (APOE) 单倍型 (与tom40相邻) 对笼子样本中的认知衰老具有显着影响 (P = 2.18 × 10(-8); 女性,P = 1.66 × 10(-11); 男性,P = 0.01)。Tom40/APOE区域的精细SNP图谱将APOE (rs429358; P = 3.66 × 10(-11)) 和tom40 (rs11556505; P = 2.45 × 10(-8)) 识别为与认知衰老相关的基因座。发现和复制队列中的插补和条件分析强烈表明,这种效应是由于APOE引起的 (rs429358)。功能基因组分析表明,tom40/APOE区域的snp具有功能性,调节的非蛋白质编码作用。APOE区域与非病理性认知老化显着相关。一种或多种因果变异的身份和机制仍不清楚。

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