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Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus

Molecular Psychiatry volume 20, pages 1588–1595 (2015)Cite this article

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Abstract

We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration.

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Acknowledgements

We would like to thank Drs. Irene Litvan, Subhojit Roy and Marilyn Albert for helpful comments on an earlier version of this manuscript. This research was supported by grants from the National Institutes of Health (R01AG031224, K01AG029218, K02NS067427, T32 EB005970, UO1AG032984, U24-AG041689, and R01 MH100351), the Research Council of Norway (#213837, #225989, #223273, #237250/EU JPND), the South East Norway Health Authority (2013-123), the Norwegian Health Association and the KG Jebsen Foundation. AJS was supported by NIH grants RC2DA029475 and R01HD061414 and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship. Please see Supplementary Acknowledgements for ADGC and ADNI funding sources.

Author information

Author notes

  1. R S Desikan, A J Schork, Y Wang, A Witoelar, M Sharma, L K McEvoy, D Holland, J B Brewer, C-H Chen, W K Thompson, D Harold, J Williams, M J Owen, M C O'Donovan, M A Pericak-Vance, R Mayeux, J L Haines, L A Farrer, G D Schellenberg, P Heutink, A B Singleton, A Brice, N W Wood, J Hardy, M Martinez, S H Choi, A DeStefano, M A Ikram, J C Bis, A Smith, A L Fitzpatrick, L Launer, C van Duijn, S Seshadri, I D Ulstein, D Aarsland, T Fladby, S Djurovic, B T Hyman, J Snaedal, H Stefansson, K Stefansson, T Gasser, O A Andreassen and A M Dale: R S Desikan, A J Schork, Y Wang, A Witoelar, M Sharma, L K McEvoy, D Holland, J B Brewer, C-H Chen, W K Thompson, D Harold, J Williams, M J Owen, M C O'Donovan, M A Pericak-Vance, R Mayeux, J L Haines, L A Farrer, G D Schellenberg, P Heutink, A B Singleton, A Brice, N W Wood, J Hardy, M Martinez, S H Choi, A DeStefano, M A Ikram, J C Bis, A Smith, A L Fitzpatrick, L Launer, C van Duijn, S Seshadri, I D Ulstein, D Aarsland, T Fladby, S Djurovic, B T Hyman, J Snaedal, H Stefansson, K Stefansson, T Gasser, O A Andreassen and A M Dale: Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://www.loni.usc.edu/ADNI/Data/ADNI_Authorship_List.pdf.

  2. Full list of investigators included in the Supplemental materials.

Authors and Affiliations

  1. Department of Radiology, University of California, San Diego, La Jolla, , CA, USA

    R S Desikan, L K McEvoy, J B Brewer, C-H Chen & A M Dale

  2. Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA

    A J Schork & A M Dale

  3. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Y Wang, D Holland, J B Brewer & A M Dale

  4. NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital,

    Y Wang, A Witoelar, S Djurovic & O A Andreassen

  5. Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    Y Wang, A Witoelar, S Djurovic & O A Andreassen

  6. Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research University of Tubingen, Tubingen, Germany

    M Sharma & T Gasser

  7. Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany

    M Sharma

  8. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    C-H Chen, W K Thompson, O A Andreassen & A M Dale

  9. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, UK

    D Harold, J Williams, M J Owen & M C O'Donovan

  10. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA

    M A Pericak-Vance

  11. Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA

    R Mayeux

  12. Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    J L Haines

  13. Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA

    L A Farrer

  14. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    G D Schellenberg

  15. German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Paul-Ehrlich-Straße 15, Tübingen, Germany

    P Heutink

  16. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA

    A B Singleton

  17. Sorbonne Université, UPMC Univ Paris 06, Paris, France

    A Brice

  18. UCL Genetics Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

    N W Wood

  19. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

    J Hardy

  20. INSERM UMR1043, CPTP, CHU Purpan, Toulouse, France

    M Martinez

  21. Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA

    S H Choi & A DeStefano

  22. The National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    A DeStefano & S Seshadri

  23. Deparment of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands

    M A Ikram & C van Duijn

  24. Deparment of Internal Medicine, University of Washington, Seattle, WA, USA

    J C Bis

  25. Icelandic Heart Association, Kopavogur, Iceland

    A Smith

  26. Department of Epidemiology, University of Washington, Seattle, WA, USA

    A L Fitzpatrick

  27. Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC, USA

    L Launer

  28. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    S Seshadri

  29. Department of Old Age Psychiatry, Norwegian Centre for Dementia Research, Oslo University Hospital, Oslo, Norway

    I D Ulstein

  30. Department of Geriatric Psychiatry, Akershus University Hospital, Oslo, Norway

    D Aarsland

  31. Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway

    D Aarsland

  32. Department of Neurobiology, Alzheimer's Disease Research Centre, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden

    D Aarsland

  33. Institute of Clinical Medicine, University of Oslo,, Oslo, Norway

    T Fladby

  34. Department of Neurology, Akershus University Hospital, Oslo, Norway

    T Fladby

  35. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    B T Hyman

  36. Department of Geriatric Medicine, University Hospital Reykjavik, Reykjavik, Iceland

    J Snaedal

  37. deCODE Genetics/Amgen, Reykjavik, Iceland

    H Stefansson & K Stefansson

  38. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    K Stefansson

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  1. R S Desikan
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  7. D Holland
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  11. D Harold
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  12. J Williams
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  13. M J Owen
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  14. M C O'Donovan
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  15. M A Pericak-Vance
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  19. G D Schellenberg
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  42. K Stefansson
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  43. T Gasser
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  44. O A Andreassen
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  45. A M Dale
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for the ADNI ADGC, GERAD, CHARGE and IPDGC Investigators

Corresponding authors

Correspondence to R S Desikan, O A Andreassen or A M Dale.

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Competing interests

Disclosures Dr. Anders M. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives funding through research agreements with General Electric Healthcare (GEHC) and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Dr. Linda K. McEvoy has stock options in CorTechs Labs, Inc. Dr. James B. Brewer holds stock options in CorTechs Labs, Inc and serves on the advisory board and receives financial support from the Eli Lilly Biomarker Unit (Amyvid). Dr. Brewer also receives research support from General Electric and Janssen Alzheimer Immunotherapy.

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Desikan, R., Schork, A., Wang, Y. et al. Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus. Mol Psychiatry 20, 1588–1595 (2015). https://doi.org/10.1038/mp.2015.6

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