TY  - JOUR
AU  - Pottier, Cyril
AU  - Küçükali, Fahri
AU  - Baker, Matt
AU  - Batzler, Anthony
AU  - Jenkins, Gregory D
AU  - van Blitterswijk, Marka
AU  - Vicente, Cristina T
AU  - De Coster, Wouter
AU  - Wynants, Sarah
AU  - Van de Walle, Pieter
AU  - Ross, Owen A
AU  - Murray, Melissa E
AU  - Faura, Júlia
AU  - Haggarty, Stephen J
AU  - van Rooij, Jeroen Gj
AU  - Mol, Merel O
AU  - Hsiung, Ging-Yuek R
AU  - Graff, Caroline
AU  - Öijerstedt, Linn
AU  - Neumann, Manuela
AU  - Asmann, Yan
AU  - McDonnell, Shannon K
AU  - Baheti, Saurabh
AU  - Josephs, Keith A
AU  - Whitwell, Jennifer L
AU  - Bieniek, Kevin F
AU  - Forsberg, Leah
AU  - Heuer, Hilary
AU  - Lago, Argentina Lario
AU  - Geier, Ethan G
AU  - Yokoyama, Jennifer S
AU  - Oddi, Alexis P
AU  - Flanagan, Margaret
AU  - Mao, Qinwen
AU  - Hodges, John R
AU  - Kwok, John B
AU  - Domoto-Reilly, Kimiko
AU  - Synofzik, Matthis
AU  - Wilke, Carlo
AU  - Onyike, Chiadi
AU  - Dickerson, Bradford C
AU  - Evers, Bret M
AU  - Dugger, Brittany N
AU  - Munoz, David G
AU  - Keith, Julia
AU  - Zinman, Lorne
AU  - Rogaeva, Ekaterina
AU  - Suh, EunRan
AU  - Gefen, Tamar
AU  - Geula, Changiz
AU  - Weintraub, Sandra
AU  - Diehl-Schmid, Janine
AU  - Farlow, Martin R
AU  - Edbauer, Dieter
AU  - Woodruff, Bryan K
AU  - Caselli, Richard J
AU  - Donker Kaat, Laura L
AU  - Huey, Edward D
AU  - Reiman, Eric M
AU  - Mead, Simon
AU  - King, Andrew
AU  - Roeber, Sigrun
AU  - Nana, Alissa L
AU  - Ertekin-Taner, Nilufer
AU  - Knopman, David S
AU  - Petersen, Ronald C
AU  - Petrucelli, Leonard
AU  - Uitti, Ryan J
AU  - Wszolek, Zbigniew K
AU  - Ramos, Eliana Marisa
AU  - Grinberg, Lea T
AU  - Tempini, Maria Luisa Gorno
AU  - Rosen, Howard J
AU  - Spina, Salvatore
AU  - Piguet, Olivier
AU  - Grossman, Murray
AU  - Trojanowski, John Q
AU  - Keene, C Dirk
AU  - Jin, Lee-Way
AU  - Prudlo, Johannes
AU  - Geschwind, Daniel H
AU  - Rissman, Robert A
AU  - Cruchaga, Carlos
AU  - Ghetti, Bernardino
AU  - Halliday, Glenda M
AU  - Beach, Thomas G
AU  - Serrano, Geidy E
AU  - Arzberger, Thomas
AU  - Herms, Jochen
AU  - Boxer, Adam L
AU  - Honig, Lawrence S
AU  - Vonsattel, Jean P
AU  - Lopez, Oscar L
AU  - Kofler, Julia
AU  - White, Charles L
AU  - Gearing, Marla
AU  - Glass, Jonathan
AU  - Rohrer, Jonathan D
AU  - Irwin, David J
AU  - Lee, Edward B
AU  - Van Deerlin, Vivianna
AU  - Castellani, Rudolph
AU  - Mesulam, Marsel M
AU  - Tartaglia, Maria C
AU  - Finger, Elizabeth C
AU  - Troakes, Claire
AU  - Al-Sarraj, Safa
AU  - Dalgard, Clifton L
AU  - Miller, Bruce L
AU  - Seelaar, Harro
AU  - Graff-Radford, Neill R
AU  - Boeve, Bradley F
AU  - Mackenzie, Ian Ra
AU  - van Swieten, John C
AU  - Seeley, William W
AU  - Sleegers, Kristel
AU  - Dickson, Dennis W
AU  - Biernacka, Joanna M
AU  - Rademakers, Rosa
TI  - Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00559
SP  - 3914
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Whole Genome Sequencing
KW  - Risk Factors
KW  - Genetic Predisposition to Disease
KW  - Male
KW  - Female
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Aged
KW  - Middle Aged
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Cohort Studies
KW  - Nerve Tissue Proteins: genetics
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - TARDBP protein, human (NLM Chemicals)
KW  - TBK1 protein, human (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40280976
C2  - pmc:PMC12032271
DO  - DOI:10.1038/s41467-025-59216-0
UR  - https://pub.dzne.de/record/278068
ER  -