Document Detail

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.
MedLine Citation:
PMID:  23207651     Owner:  NLM     Status:  MEDLINE    
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.
G Davies; S E Harris; C A Reynolds; A Payton; H M Knight; D C Liewald; L M Lopez; M Luciano; A J Gow; J Corley; R Henderson; C Murray; A Pattie; H C Fox; P Redmond; M W Lutz; O Chiba-Falek; C Linnertz; S Saith; P Haggarty; G McNeill; X Ke; W Ollier; M Horan; A D Roses; C P Ponting; D J Porteous; A Tenesa; A Pickles; J M Starr; L J Whalley; N L Pedersen; N Pendleton; P M Visscher; I J Deary
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-04
Journal Detail:
Title:  Molecular psychiatry     Volume:  19     ISSN:  1476-5578     ISO Abbreviation:  Mol. Psychiatry     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2013-12-23     Completed Date:  2014-08-26     Revised Date:  2014-10-28    
Medline Journal Info:
Nlm Unique ID:  9607835     Medline TA:  Mol Psychiatry     Country:  England    
Other Details:
Languages:  eng     Pagination:  76-87     Citation Subset:  IM    
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MeSH Terms
Aging / genetics*
Apolipoproteins E / genetics*
Cognition / physiology*
Cohort Studies
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Linkage Disequilibrium
Membrane Transport Proteins / genetics
Polymorphism, Single Nucleotide / genetics*
Grant Support
AG 04563/AG/NIA NIH HHS; AG028555/AG/NIA NIH HHS; AG04563/AG/NIA NIH HHS; AG08724/AG/NIA NIH HHS; AG08861/AG/NIA NIH HHS; AG10175/AG/NIA NIH HHS; BB/F022441/1//Biotechnology and Biological Sciences Research Council; CZB/4/505//Chief Scientist Office; ETM/55//Chief Scientist Office; G0100266//Medical Research Council; G0100594//Medical Research Council; G0400546//Medical Research Council; G0700704//Medical Research Council; G0701120//Medical Research Council; G0901461//Medical Research Council; G1001375//Medical Research Council; //Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/Apolipoproteins E; 0/Membrane Transport Proteins; 0/TOMM40 protein, human

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