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09.02.2019 | Original Paper

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

verfasst von: Cyril Pottier, Yingxue Ren, Ralph B. Perkerson III, Matt Baker, Gregory D. Jenkins, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Jeroen G. J. van Rooij, Melissa E. Murray, Elizabeth Christopher, Shannon K. McDonnell, Zachary Fogarty, Anthony Batzler, Shulan Tian, Cristina T. Vicente, Billie Matchett, Anna M. Karydas, Ging-Yuek Robin Hsiung, Harro Seelaar, Merel O. Mol, Elizabeth C. Finger, Caroline Graff, Linn Öijerstedt, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Johannes Prudlo, Patrizia Rizzu, Javier Simon-Sanchez, Dieter Edbauer, Sigrun Roeber, Janine Diehl-Schmid, Bret M. Evers, Andrew King, M. Marsel Mesulam, Sandra Weintraub, Changiz Geula, Kevin F. Bieniek, Leonard Petrucelli, Geoffrey L. Ahern, Eric M. Reiman, Bryan K. Woodruff, Richard J. Caselli, Edward D. Huey, Martin R. Farlow, Jordan Grafman, Simon Mead, Lea T. Grinberg, Salvatore Spina, Murray Grossman, David J. Irwin, Edward B. Lee, EunRan Suh, Julie Snowden, David Mann, Nilufer Ertekin-Taner, Ryan J. Uitti, Zbigniew K. Wszolek, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, John R. Hodges, Olivier Piguet, Ethan G. Geier, Jennifer S. Yokoyama, Robert A. Rissman, Ekaterina Rogaeva, Julia Keith, Lorne Zinman, Maria Carmela Tartaglia, Nigel J. Cairns, Carlos Cruchaga, Bernardino Ghetti, Julia Kofler, Oscar L. Lopez, Thomas G. Beach, Thomas Arzberger, Jochen Herms, Lawrence S. Honig, Jean Paul Vonsattel, Glenda M. Halliday, John B. Kwok, Charles L. White III, Marla Gearing, Jonathan Glass, Sara Rollinson, Stuart Pickering-Brown, Jonathan D. Rohrer, John Q. Trojanowski, Vivianna Van Deerlin, Eileen H. Bigio, Claire Troakes, Safa Al-Sarraj, Yan Asmann, Bruce L. Miller, Neill R. Graff-Radford, Bradley F. Boeve, William W. Seeley, Ian R. A. Mackenzie, John C. van Swieten, Dennis W. Dickson, Joanna M. Biernacka, Rosa Rademakers

Erschienen in: Acta Neuropathologica | Ausgabe 6/2019

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Abstract

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

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Titel: Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
verfasst von: Cyril Pottier
Yingxue Ren
Ralph B. Perkerson III
Matt Baker
Gregory D. Jenkins
Marka van Blitterswijk
Mariely DeJesus-Hernandez
Jeroen G. J. van Rooij
Melissa E. Murray
Elizabeth Christopher
Shannon K. McDonnell
Zachary Fogarty
Anthony Batzler
Shulan Tian
Cristina T. Vicente
Billie Matchett
Anna M. Karydas
Ging-Yuek Robin Hsiung
Harro Seelaar
Merel O. Mol
Elizabeth C. Finger
Caroline Graff
Linn Öijerstedt
Manuela Neumann
Peter Heutink
Matthis Synofzik
Carlo Wilke
Johannes Prudlo
Patrizia Rizzu
Javier Simon-Sanchez
Dieter Edbauer
Sigrun Roeber
Janine Diehl-Schmid
Bret M. Evers
Andrew King
M. Marsel Mesulam
Sandra Weintraub
Changiz Geula
Kevin F. Bieniek
Leonard Petrucelli
Geoffrey L. Ahern
Eric M. Reiman
Bryan K. Woodruff
Richard J. Caselli
Edward D. Huey
Martin R. Farlow
Jordan Grafman
Simon Mead
Lea T. Grinberg
Salvatore Spina
Murray Grossman
David J. Irwin
Edward B. Lee
EunRan Suh
Julie Snowden
David Mann
Nilufer Ertekin-Taner
Ryan J. Uitti
Zbigniew K. Wszolek
Keith A. Josephs
Joseph E. Parisi
David S. Knopman
Ronald C. Petersen
John R. Hodges
Olivier Piguet
Ethan G. Geier
Jennifer S. Yokoyama
Robert A. Rissman
Ekaterina Rogaeva
Julia Keith
Lorne Zinman
Maria Carmela Tartaglia
Nigel J. Cairns
Carlos Cruchaga
Bernardino Ghetti
Julia Kofler
Oscar L. Lopez
Thomas G. Beach
Thomas Arzberger
Jochen Herms
Lawrence S. Honig
Jean Paul Vonsattel
Glenda M. Halliday
John B. Kwok
Charles L. White III
Marla Gearing
Jonathan Glass
Sara Rollinson
Stuart Pickering-Brown
Jonathan D. Rohrer
John Q. Trojanowski
Vivianna Van Deerlin
Eileen H. Bigio
Claire Troakes
Safa Al-Sarraj
Yan Asmann
Bruce L. Miller
Neill R. Graff-Radford
Bradley F. Boeve
William W. Seeley
Ian R. A. Mackenzie
John C. van Swieten
Dennis W. Dickson
Joanna M. Biernacka
Rosa Rademakers
Publikationsdatum: 09.02.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 6/2019
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-01962-9

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Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

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