A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.
A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.
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DOI：
10.1038/mp.2012.159
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发表时间：
2014-01
影响因子：
11
通讯作者：
Deary IJ
中科院分区：
文献类型：
--
作者：
Davies G;Harris SE;Reynolds CA;Payton A;Knight HM;Liewald DC;Lopez LM;Luciano M;Gow AJ;Corley J;Henderson R;Murray C;Pattie A;Fox HC;Redmond P;Lutz MW;Chiba-Falek O;Linnertz C;Saith S;Haggarty P;McNeill G;Ke X;Ollier W;Horan M;Roses AD;Ponting CP;Porteous DJ;Tenesa A;Pickles A;Starr JM;Whalley LJ;Pedersen NL;Pendleton N;Visscher PM;Deary IJ
认知能力下降是变老的一个可怕方面。它是导致老年人生活质量下降和丧失独立性的一个主要因素。我们调查了5组老年人非病理性认知老化的个体差异的遗传贡献。我们在英格兰和苏格兰认知老化遗传学（CAGES）项目中对3511名无关成年人进行了549692个单核苷酸多态性（SNP）的全基因组关联分析。这些人有详细的纵向认知数据，从这些数据中构建了测量每个人认知变化的表型。位于TOMM 40的一个SNP-rs 2075650与认知老化有着全基因组的显著关联（p = 2.5 × 10−8）。这一结果在三个独立的瑞典队列的荟萃分析中得到了重复（p = 2.41 × 10−6）。APOE单倍型（与TOMM 40相邻），以前与认知老化相关，在CAGES样本中对认知老化有显著影响（p = 2.18 × 10−8;女性，p = 1.66 × 10−11;男性，p = 0.01）。TOMM 40/APOE区域的精细SNP定位确定了APOE（rs 429358; p = 3.66 × 10−11）和TOMM 40（rs 11556505; p = 2.45 × 10−8）作为与认知老化相关的基因座。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（rs 429358）。功能基因组分析表明，TOMM 40/APOE区域的SNPs具有功能性、调节性非蛋白编码效应。APOE区域与非病理性认知老化显著相关。一个或多个致病变体的身份和机制仍不清楚。
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 non-pathological 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—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 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 non-pathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
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影响因子：
5.3
作者：
Green, Michael F.
通讯作者：
Green, Michael F.
影响因子：
4.1
作者：
Deary IJ;Gow AJ;Taylor MD;Corley J;Brett C;Wilson V;Campbell H;Whalley LJ;Visscher PM;Porteous DJ;Starr JM
通讯作者：
Starr JM
APOE 位点遗传变异的功能分析表明区域增强子参与 TOMM40 和 APOE 的调节。
影响因子：
3.5
作者：
通讯作者：
--
影响因子：
4
作者：
Finkel, Deborah;Reynolds, Chandra A.;McArdle, John J.;Hamagami, Fumiaki;Pedersen, Nancy L.
通讯作者：
Pedersen, Nancy L.
影响因子：
64.8
作者：
Deary, Ian J.;Yang, Jian;Visscher, Peter M.
通讯作者：
Visscher, Peter M.