Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
Cyril Pottier, Fahri Küçükali, Matt Baker, Anthony Batzler, Gregory D. Jenkins, Marka van Blitterswijk, Cristina T. Vicente, Wouter De Coster, Sarah Wynants, Pieter Van de Walle, Owen A. Ross, Melissa E. Murray, Júlia Faura, Stephen J. Haggarty, Jeroen van Rooij, Merel O. Mol, Ging‐Yuek Robin Hsiung, Caroline Graff, Linn Öijerstedt, Manuela Neumann, Yan W. Asmann, Shannon K. McDonnell, Saurabh Baheti, Keith A. Josephs, Jennifer Whitwell, Kevin F. Bieniek, Leah K. Forsberg, Hilary W. Heuer, Argentina Lario Lago, Ethan G. Geier, Jennifer S. Yokoyama, Alexis P. Oddi, Margaret E. Flanagan, Qinwen Mao, John R. Hodges, John B. Kwok, Kimiko Domoto‐Reilly, Matthis Synofzik, Carlo Wilke, Chiadi U. Onyike, Bradford C. Dickerson, Bret M. Evers, Brittany N. Dugger, David G. Muñoz, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, EunRan Suh, Tamar Gefen, Changiz Geula, Sandra Weıntraub, Janine Diehl‐Schmid, Martin R. Farlow, Dieter Edbauer, Bryan K. Woodruff, Richard J. Caselli, Laura L. Donker Kaat, Edward D. Huey, Eric M. Reiman, Simon Mead, Andrew King, Sigrun Roeber, Alissa L. Nana, Nilüfer Ertekin‐Taner, David S. Knopman, Ronald C. Petersen, Leonard Petrucelli, Ryan J. Uitti, Zbigniew K. Wszołek, Eliana Marisa Ramos, Lea T. Grinberg, Maria Luisa Gorno Tempini, Howard J. Rosen, Salvatore Spina, Olivier Piguet, Murray Grossman, John Q. Trojanowski, C. Dirk Keene, Lee‐Way Jin, Johannes Prudlo, Daniel H. Geschwind, Robert A. Rissman, Carlos Cruchaga, Bernardino Ghetti, Glenda M. Halliday, Thomas G. Beach, Geidy E. Serrano, Thomas Arzberger, Jochen Herms, Adam L. Boxer, Lawrence S. Honig, Jean Paul Vonsattel, Oscar L. López, Julia Kofler, Charles L. White, Marla Gearing, Jonathan D. Glass, Jonathan D. Rohrer, David J. Irwin, Edward B. Lee
Abstract
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications. Here the authors identify TNIP1 as a risk factor for a fatal neurodegenerative disorder and discover specific genetic loci associated with the three main subtypes of this disorder. The findings highlight distinct disease mechanisms, emphasizing the roles of immunity and the notch signaling pathway.