Original Article | Published:

Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies

Molecular Psychiatry volume 23, pages 15211529 (2018) | Download Citation

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Abstract

Tauopathies, including Alzheimer’s disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10−8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid β plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid β plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

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Acknowledgements

We thank all the participants of the Religious Orders Study the Rush Memory and Aging Project and the Adult Changes in Thought, as well as the staff at the Rush Alzheimer’s Disease Center for this work. This work was supported by the National Institutes of Health (Grants P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG36836, K25AG041906 and U01AG46152).

Author contributions

CDK, JS and JAS collected, prepared and generated data from the samples. LBC, CCW, TR and LY performed analyses on the resulting data. SM, EBL, TJM, CDK, JS and PKC generated and analyzed the replication data. EBL, TJM and PKC designed the replication study. PLD and DAB designed the primary study. PLD, CCW, JMS and LBC wrote the manuscript. All of the authors critically reviewed the manuscript.

Author information

Author notes

    • D A Bennett
    •  & P L De Jager

    These authors contributed equally to this work.

Affiliations

  1. Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women’s Hospital, Boston, MA, USA

    • L B Chibnik
    • , C C White
    • , T Raj
    •  & P L De Jager
  2. Department of Neurology, Harvard Medical School, Boston, MA, USA

    • L B Chibnik
    •  & P L De Jager
  3. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • L B Chibnik
    • , C C White
    • , T Raj
    •  & P L De Jager
  4. Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA

    • L B Chibnik
  5. Department of Medicine, University of Washington, Seattle, WA, USA

    • S Mukherjee
    •  & P K Crane
  6. Rush Alzheimer’s Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA

    • L Yu
    • , J A Schneider
    •  & D A Bennett
  7. Group Health Research Institute, Seattle, WA, USA

    • E B Larson
  8. Department of Pathology, University of Washington, Seattle, WA, USA

    • T J Montine
    •  & C D Keene
  9. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    • J Sonnen
  10. Departments of Neurology, Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA

    • J M Shulman
  11. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    • J M Shulman

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Competing interests

Dr Schneider is a consultant for Navidea Biopharmaceuticals and an advisor to Eli Lilly and Genetech. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to P L De Jager.

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DOI

https://doi.org/10.1038/mp.2017.20

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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