Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing
Authors: Pottier Cyril , Küçükali Fahri , Baker Matt , Batzler Anthony , Jenkins Gregory D. , van Blitterswijk Marka , Vicente Cristina T. , De Coster Wouter , Wynants Sarah , Van de Walle Pieter , Ross Owen A. , Murray Melissa E. , Faura Júlia , Haggarty Stephen J. , van Rooij Jeroen GJ. , Mol Merel O. , Hsiung Ging-Yuek R. , Graff Caroline , Öijerstedt Linn , Neumann Manuela , Asmann Yan , McDonnell Shannon K. , Baheti Saurabh , Josephs Keith A. , Whitwell Jennifer L. , Bieniek Kevin F. , Forsberg Leah , Heuer Hilary , Lago Argentina Lario , Geier Ethan G. , Yokoyama Jennifer S. , Oddi Alexis P. , Flanagan Margaret , Mao Qinwen , Hodges John R. , Kwok John B. , Domoto-Reilly Kimiko , Synofzik Matthis , Wilke Carlo , Onyike Chiadi , Dickerson Bradford C. , Evers Bret M. , Dugger Brittany N. , Munoz David G. , Keith Julia , Zinman Lorne , Rogaeva Ekaterina , Suh EunRan , Gefen Tamar , Geula Changiz , Weintraub Sandra , Diehl-Schmid Janine , Farlow Martin R. , Edbauer Dieter , Woodruff Bryan K. , Caselli Richard J. , Donker Kaat Laura L. , Huey Edward D. , Reiman Eric M. , Mead Simon , King Andrew , Roeber Sigrun , Nana Alissa L. , Ertekin-Taner Nilufer , Knopman David S. , Petersen Ronald C. , Petrucelli Leonard , Uitti Ryan J. , Wszolek Zbigniew K. , Ramos Eliana Marisa , Grinberg Lea T. , Gorno Tempini Maria Luisa , Rosen Howard J. , Spina Salvatore , Piguet Olivier , Grossman Murray , Trojanowski John Q. , Keene Dirk C. , Lee-Way Jin , Prudlo Johannes , Geschwind Daniel H. , Rissman Robert A. , Cruchaga Carlos , Ghetti Bernardino , Halliday Glenda M. , Beach Thomas G. , Serrano Geidy E. , Arzberger Thomas , Herms Jochen , Boxer Adam L. , Honig Lawrence S. , Vonsattel Jean P. , Lopez Oscar L. , Kofler Julia , White Charles L. , Gearing Marla , Glass Jonathan , Rohrer Jonathan D. , Irwin David J. , Lee Edward B. , Van Deerlin Vivianna , Castellani Rudolph , Mesulam Marsel M. , Tartaglia Maria C. , Finger Elizabeth C. , Troakes Claire , Al-Sarraj Safa , Miller Bruce L. , Seelaar Harro , Graff-Radford Neill R. , Boeve Bradley F. , Mackenzie Ian RA. , van Swieten John C. , Seeley William W. , Sleegers Kristel , Dickson Dennis W. , Biernacka Joanna M. , Rademakers Rosa 
Published: June 2024

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 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirmUNC13Aas the strongest overall FTLD-TDP risk factor and identifyTNIP1as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time 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 confirmedTBK1and identifiedVIPR1,RBPJL, andL3MBTL1as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.