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

Davies, G., Harris, S. E., Reynolds, C. A., Payton, A., Knight, H. M., Liewald, D. C., Lopez, L. M., Luciano, M., Gow, A. J., Corley, J., Henderson, R., Murray, C., 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, N. L., Pendleton, N., Visscher, P. M. and Deary, I. J. (2012) A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Molecular Psychiatry, 19 1: 76-87. doi:10.1038/mp.2012.159

Author Davies, G.
Harris, S. E.
Reynolds, C. A.
Payton, A.
Knight, H. M.
Liewald, D. C.
Lopez, L. M.
Luciano, M.
Gow, A. J.
Corley, J.
Henderson, R.
Murray, C.
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, N. L.
Pendleton, N.
Visscher, P. M.
Deary, I. J.
Title A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
Publication date 2012-12-04
Year available 2012
Sub-type Article (original research)
DOI 10.1038/mp.2012.159
Open Access Status DOI
Volume 19
Issue 1
Start page 76
End page 87
Total pages 12
Place of publication London, United Kingdom
Publisher Nature
Collection year 2013
Language eng
Formatted 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.
Keyword APOE
Cognitive ageing
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Advance online publication: 4 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
UQ Diamantina Institute Publications
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Created: Tue, 12 Feb 2013, 15:34:09 EST by Debra McMurtrie on behalf of Queensland Brain Institute