title: A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.
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.
authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
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authors.lastname: Davies
authors.affiliation: 1] Medical Genetics Section, The University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Department of Psychology, University of California, Riverside, Riverside, CA, USA.
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authors.initials: CA
authors.lastname: Reynolds
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
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authors.affiliation: CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
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authors.initials: HM
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authors.affiliation: 1] Department of Psychology, The University of Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: D C
authors.initials: DC
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authors.affiliation: 1] Department of Psychology, The University of Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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authors.affiliation: 1] Department of Psychology, The University of Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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authors.lastname: Luciano
authors.affiliation: 1] Department of Psychology, The University of Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Corley
authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: R
authors.initials: R
authors.lastname: Henderson
authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: C
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authors.lastname: Murray
authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: A
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authors.lastname: Pattie
authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
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authors.initials: HC
authors.lastname: Fox
authors.affiliation: Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: P
authors.initials: P
authors.lastname: Redmond
authors.affiliation: 1] Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA [2] Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: 1] Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA [2] Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC, USA.
authors.forename: O
authors.initials: O
authors.lastname: Chiba-Falek
authors.affiliation: Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
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authors.affiliation: Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
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authors.initials: S
authors.lastname: Saith
authors.affiliation: Nutrition and Epigenetics Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
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authors.lastname: Haggarty
authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: G
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authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: X
authors.initials: X
authors.lastname: Ke
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Ollier
authors.affiliation: School of Community-Based Medicine, Neurodegeneration Research Group, University of Manchester, Clinical sciences Building, Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Horan
authors.affiliation: 1] Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA [2] Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, NC, USA [3] Zinfandel Pharmaceuticals, Chapel Hill, NC, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Roses
authors.affiliation: CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: C P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: 1] Medical Genetics Section, The University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: 1] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK [2] The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Clinical Trials Unit, Institute of Psychiatry, London, UK.
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authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK [2] Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, UK.
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authors.initials: JM
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authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
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authors.initials: LJ
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authors.forename: N L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: School of Community-Based Medicine, Neurodegeneration Research Group, University of Manchester, Clinical sciences Building, Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: N
authors.initials: N
authors.lastname: Pendleton
authors.affiliation: 1] Queensland Institute of Medical Research, Brisbane, Queensland, Australia [2] University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia [3] The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: 1] Department of Psychology, The University of Edinburgh, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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mesh_terms: D000375:Aging / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D004739:England; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012606:Scotland
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human