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

Molecular Psychiatry volume 19, pages 76–87 (2014)Cite this article

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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.

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Acknowledgements

We thank the cohort participants who contributed to these studies. We thank Martha Pollard for Lothian Birth Cohort 1921 data collection. Genotyping of the CAGES cohorts and the analyses conducted here were supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK The Disconnected Mind project). Phenotype collection in the Aberdeen Birth Cohort 1936 was supported by BBSRC, the Wellcome Trust and the Alzheimer’s Research Trust. Phenotype collection in the Manchester and Newcastle Longitudinal Studies of Cognitive Ageing cohorts was supported by Social Science Research Council, Medical Research Council, Economic and Social Research Council, Research Into Ageing, Wellcome Trust and Unilever. We gratefully acknowledge the support of the Swedish Research Council (2009–2298), National Institute on Aging (AG 04563, AG10175, AG08861, AG08724, AG028555). The Australian-based researcher acknowledges support from the Australian Research Council and the National Health and Medical Research Council. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. This work was funded by the Biotechnology and Biological Sciences Research Council, The Royal Society, The Chief Scientist Office of the Scottish Government, Research Into Ageing, Age UK, the Wellcome Trust, the Alzheimer’s Research Trust, Social Science Research Council, Medical Research Council, Economic and Social Research Council, Unilever and the Engineering and Physical Sciences Research Council. Work with the Swedish samples was supported by the Swedish Research Council (2009–2298), and the US National Institute on Aging (AG04563, AG10175, AG08861, AG08724, AG028555). PMV is supported by the Australian National Health and Medical Research Council.

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Authors and Affiliations

  1. Department of Psychology, The University of Edinburgh, Edinburgh, UK

    G Davies, D C Liewald, L M Lopez, M Luciano, A J Gow, J Corley, R Henderson, C Murray, A Pattie, P Redmond & I J Deary

  2. Medical Genetics Section, The University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital Edinburgh, Edinburgh, UK

    S E Harris & D J Porteous

  3. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK

    S E Harris, D C Liewald, L M Lopez, M Luciano, A J Gow, D J Porteous, J M Starr & I J Deary

  4. Department of Psychology, University of California, Riverside, Riverside, CA, USA

    C A Reynolds

  5. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK

    A Payton & W Ollier

  6. Department of Physiology, CGAT, MRC Functional Genomics Unit, Anatomy and Genetics, University of Oxford, Oxford, UK

    H M Knight & C P Ponting

  7. Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK

    H C Fox, G McNeill & L J Whalley

  8. Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    M W Lutz, O Chiba-Falek, C Linnertz, S Saith & A D Roses

  9. Joseph and Kathleen Bryan Alzheimer’s Disease Research Center, Duke University, Durham, NC, USA

    M W Lutz, O Chiba-Falek & A D Roses

  10. Nutrition and Epigenetics Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK

    P Haggarty

  11. Institute of Child Health, University College London, London, UK

    X Ke

  12. School of Community-Based Medicine, Neurodegeneration Research Group, University of Manchester, Clinical sciences Building, Salford Royal NHS Foundation Trust, Salford, UK

    M Horan & N Pendleton

  13. Zinfandel Pharmaceuticals, Chapel Hill, NC, USA

    A D Roses

  14. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK

    A Tenesa

  15. The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, UK

    A Tenesa

  16. Clinical Trials Unit, Institute of Psychiatry, London, UK

    A Pickles

  17. Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, UK

    J M Starr

  18. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    N L Pedersen

  19. Department of Psychology, University of Southern California, Los Angeles, CA, USA

    N L Pedersen

  20. Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    P M Visscher

  21. University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia

    P M Visscher

  22. The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia

    P M Visscher

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  1. G Davies
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  28. A Tenesa
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  29. A Pickles
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  35. I J Deary
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Correspondence to I J Deary.

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Competing interests

Allen D Roses is the CEO and only stock holder of Zinfandel Pharmaceuticals, a company in an Alliance with Takeda Pharmaceuticals, to perform the prospective qualification of the TOMM40 marker for age of onset distribution of Alzheimer’s Disease. For this study, Zinfandel Pharmaceuticals paid for the TOMM40 assays to be performed for medical research, not as a clinical diagnostic.

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Davies, G., Harris, S., Reynolds, C. et al. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry 19, 76–87 (2014). https://doi.org/10.1038/mp.2012.159

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