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

Cyril Pottier, Yingxue Ren, Ralph B. Perkerson, 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. MolElizabeth 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, Eun Ran 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, 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

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)879-899
Number of pages21
JournalActa Neuropathologica
Issue number6
StatePublished - Jun 1 2019


  • DPP6
  • HLA
  • Immunity
  • TBK1
  • UNC13A
  • Whole-genome sequencing FTLD-TDP

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine


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