A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing

Gail Davies, Sarah E Harris, Chandra A Reynolds, Antony Payton, Helen M Knight, David C M Liewald, Lorna M Lopez, Michelle Carmen Luciano, Alan J Gow, Janie Corley, Ross D Henderson, Catherine L Murray, A Pattie, H C Fox, P Redmond, M W Lutz, O Chiba-Falek, C Linnertz, S Saith, P Haggarty & 15 others 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, Nancy Lee Pedersen, N Pendleton, P M Visscher, I J Deary

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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.
Original languageEnglish
Pages (from-to)76-87
Number of pages12
JournalMolecular Psychiatry
Volume19
Issue number1
Early online date4 Dec 2012
DOIs
Publication statusPublished - Jan 2014

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Genome-Wide Association Study
Apolipoproteins E
Mitochondrial Membranes
Single Nucleotide Polymorphism
Scotland
England
Nucleotide Mapping
Cognitive Aging
Individuality
Haplotypes
Meta-Analysis
Quality of Life
Genome
Phenotype

Keywords

  • APOE
  • cognitive ageing
  • genetics
  • GWAS
  • TOMM40

Cite this

Davies, G., Harris, S. E., Reynolds, C. A., Payton, A., Knight, H. M., Liewald, D. C. M., ... Deary, I. J. (2014). A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Molecular Psychiatry, 19(1), 76-87. https://doi.org/10.1038/mp.2012.159

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. / Davies, Gail; Harris, Sarah E; Reynolds, Chandra A; Payton, Antony; Knight, Helen M; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle Carmen; Gow, Alan J; Corley, Janie; Henderson, Ross D; Murray, Catherine L; Pattie, A; Fox, H C; Redmond, P; Lutz, M W; Chiba-Falek, O; Linnertz, C; Saith, S; Haggarty, P; McNeill, G; Ke, X; Ollier, W; Horan, M; Roses, A D; Ponting, C P; Porteous, D J; Tenesa, A; Pickles, A; Starr, J M; Whalley, L J; Pedersen, Nancy Lee; Pendleton, N; Visscher, P M; Deary, I J.

In: Molecular Psychiatry, Vol. 19, No. 1, 01.2014, p. 76-87.

Research output: Contribution to journalArticle

Davies, G, Harris, SE, Reynolds, CA, Payton, A, Knight, HM, Liewald, DCM, Lopez, LM, Luciano, MC, Gow, AJ, Corley, J, Henderson, RD, Murray, CL, 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 2014, 'A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing', Molecular Psychiatry, vol. 19, no. 1, pp. 76-87. https://doi.org/10.1038/mp.2012.159
Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DCM et al. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Molecular Psychiatry. 2014 Jan;19(1):76-87. https://doi.org/10.1038/mp.2012.159
Davies, Gail ; Harris, Sarah E ; Reynolds, Chandra A ; Payton, Antony ; Knight, Helen M ; Liewald, David C M ; Lopez, Lorna M ; Luciano, Michelle Carmen ; Gow, Alan J ; Corley, Janie ; Henderson, Ross D ; Murray, Catherine L ; Pattie, A ; Fox, H C ; Redmond, P ; Lutz, M W ; Chiba-Falek, O ; Linnertz, C ; Saith, S ; Haggarty, P ; McNeill, G ; Ke, X ; Ollier, W ; Horan, M ; Roses, A D ; Ponting, C P ; Porteous, D J ; Tenesa, A ; Pickles, A ; Starr, J M ; Whalley, L J ; Pedersen, Nancy Lee ; Pendleton, N ; Visscher, P M ; Deary, I J. / A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 1. pp. 76-87.
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