Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies.
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.
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.|Department of Neurology, Harvard Medical School, Boston, MA, USA.|Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
L B
LB
Chibnik
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.|Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
C C
CC
White
Department of Medicine, University of Washington, Seattle, WA, USA.
S
S
Mukherjee
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.|Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
T
T
Raj
Rush Alzheimer's Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
L
L
Yu
Group Health Research Institute, Seattle, WA, USA.
E B
EB
Larson
Department of Pathology, University of Washington, Seattle, WA, USA.
T J
TJ
Montine
Department of Pathology, University of Washington, Seattle, WA, USA.
C D
CD
Keene
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
J
J
Sonnen
Rush Alzheimer's Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
J A
JA
Schneider
Department of Medicine, University of Washington, Seattle, WA, USA.
P K
PK
Crane
Departments of Neurology, Molecular and Human Genetics, Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
J M
JM
Shulman
Rush Alzheimer's Disease Center, Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
D A
DA
Bennett
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA.|Department of Neurology, Harvard Medical School, Boston, MA, USA.|Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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PL
De Jager
D000368:Aged; D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D000069338:Neuropathology / Q000379:methods; D058225:Plaque, Amyloid / Q000378:metabolism; D011446:Prospective Studies; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism* / Q000502:physiology; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2