Davies, G and Harris, S E and Reynolds, C A and Payton, A and Knight, H M and Liewald, D C and Lopez, Lorna M. and Luciano, M and Gow, A J and Corley, J and Henderson, R and Murray, C and Pattie, A and Fox, H C and Redmond, P and Lutz, M W and Chiba-Falek, O and Linnertz, C and Saith, S and Haggarty, P and McNeill, G and Ke, X and Ollier, W and Horan, M and Roses, A D and Ponting, C P and Porteous, D J and Tenesa, A and Pickles, A and Starr, J M and Whalley, L J and Pedersen, N L and Pendleton, N and Visscher, P M and Deary, I J (2014) A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Molecular Psychiatry, 19 (1). pp. 76-87. ISSN 1359-4184

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Abstract

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.

Item Type:	Article
Keywords:	APOE; cognitive ageing; genetics; GWAS; TOMM40;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17243
Identification Number:	https://doi.org/10.1038/mp.2012.159
Depositing User:	Lorna Lopez
Date Deposited:	29 May 2023 11:47
Journal or Publication Title:	Molecular Psychiatry
Publisher:	Nature Publishing Group
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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