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

L B Chibnik^{1

2

3

4}, C C White^{1

3}, S Mukherjee⁵, T Raj^{1

3}, L Yu⁶, E B Larson⁷, T J Montine⁸, C D Keene⁸, J Sonnen⁹, J A Schneider⁶, P K Crane⁵, J M Shulman^{10

11}, D A Bennett⁶, P L De Jager^{1

2

3}

Affiliations

¹ Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Neurology, Harvard Medical School, Boston, MA, USA.
³ Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁵ Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ Rush Alzheimer's Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
⁷ Group Health Research Institute, Seattle, WA, USA.
⁸ Department of Pathology, University of Washington, Seattle, WA, USA.
⁹ Department of Pathology, University of Utah, Salt Lake City, UT, USA.
¹⁰ Departments of Neurology, Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
¹¹ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.

PMID: 28322283
PMCID: PMC5608624
DOI: 10.1038/mp.2017.20

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

L B Chibnik et al. Mol Psychiatry. 2018 Jun.

. 2018 Jun;23(6):1521-1529.

doi: 10.1038/mp.2017.20. Epub 2017 Mar 21.

Authors

Affiliations

¹ Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Neurology, Harvard Medical School, Boston, MA, USA.
³ Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁵ Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ Rush Alzheimer's Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
⁷ Group Health Research Institute, Seattle, WA, USA.
⁸ Department of Pathology, University of Washington, Seattle, WA, USA.
⁹ Department of Pathology, University of Utah, Salt Lake City, UT, USA.
¹⁰ Departments of Neurology, Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
¹¹ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.

PMID: 28322283
PMCID: PMC5608624
DOI: 10.1038/mp.2017.20

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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Conflict of interest statement

Conflict of Interest:

Dr. Schneider is a consultant for Navidea Biopharmaceuticals and an advisor to Eli Lilly Inc. and Genetech. All other authors report no conflict of interest.

Figures

**Figure 1. Regional association plot for *PTPRD* and Neurofibrillary Tangles (NFT)**
The x-axis is the base pair position and the y-axis is the −log(p-value) for the association with NFT. The blue line represents the recombination rate.

**Figure 2. Association between *PTPRD* SNP, rs560380 and Neurofibrillary Tangles**
The left plot includes all n=909 ROS and MAP brains and the right plot includes a subset of n=132 from participants with no neuritic plaques at death.

Figure 3. Regional association plot for *HS3ST4.*
The x-axis is the base pair position centered around the top pleiotropy snp, rs12597858 and the y-axis is the −log(p-value). The blue line represents the recombination rate. The bottom level shows the pleiotropic results and the top level show results for each of the seven neuropathological phenotypes.

See this image and copyright information in PMC

References

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

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

Authors

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Conflict of interest statement

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