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

Publication ,  Journal Article
Davies, G; Harris, SE; Reynolds, CA; Payton, A; Knight, HM; Liewald, DC; Lopez, LM; Luciano, M; Gow, AJ; Corley, J; Henderson, R; Murray, C ...
Published in: Mol Psychiatry
January 2014

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.

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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

January 2014

Volume

19

Issue

1

Start / End Page

76 / 87

Location

England

Related Subject Headings

  • Scotland
  • Psychiatry
  • Polymorphism, Single Nucleotide
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Linkage Disequilibrium
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
 

Citation

APA
Chicago
ICMJE
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Davies, G., Harris, S. E., Reynolds, C. A., Payton, A., Knight, H. M., Liewald, D. C., … Deary, I. J. (2014). A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry, 19(1), 76–87. https://doi.org/10.1038/mp.2012.159
Davies, G., S. E. Harris, C. A. Reynolds, A. Payton, H. M. Knight, D. C. Liewald, L. M. Lopez, et al. “A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.Mol Psychiatry 19, no. 1 (January 2014): 76–87. https://doi.org/10.1038/mp.2012.159.
Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DC, et al. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2014 Jan;19(1):76–87.
Davies, G., et al. “A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.Mol Psychiatry, vol. 19, no. 1, Jan. 2014, pp. 76–87. Pubmed, doi:10.1038/mp.2012.159.
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. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2014 Jan;19(1):76–87.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

January 2014

Volume

19

Issue

1

Start / End Page

76 / 87

Location

England

Related Subject Headings

  • Scotland
  • Psychiatry
  • Polymorphism, Single Nucleotide
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Membrane Transport Proteins
  • Male
  • Linkage Disequilibrium
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease