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 Gj van Rooij; Merel O. Mol; Ging Yuek R. Hsiung; Caroline Graff; Linn Öijerstedt; Manuela Neumann; Yan Asmann; Shannon K. McDonnell; Saurabh Baheti; Keith A. Josephs; Jennifer L. Whitwell; Kevin F. Bieniek; Leah Forsberg; Hilary Heuer; Argentina Lario Lago; Ethan G. Geier; Jennifer S. Yokoyama; Alexis P. Oddi; Margaret Flanagan; Qinwen Mao; John R. Hodges; John B. Kwok; Kimiko Domoto-Reilly; Matthis Synofzik; Carlo Wilke; Chiadi Onyike; Bradford C. Dickerson; Bret M. Evers; Brittany N. Dugger; David G. Munoz; Julia Keith; Lorne Zinman; Ekaterina Rogaeva; Eun Ran Suh; Tamar Gefen; Changiz Geula; Sandra Weintraub; 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; Nilufer Ertekin-Taner; David S. Knopman; Ronald C. Petersen; Leonard Petrucelli; Ryan J. Uitti; Zbigniew K. Wszolek; 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 P. Vonsattel; Oscar L. Lopez; Julia Kofler; Charles L. White; Marla Gearing; Jonathan Glass; Jonathan D. Rohrer; David J. Irwin; Edward B. Lee; Vivianna Van Deerlin; Rudolph Castellani; Marsel M. Mesulam; Maria C. Tartaglia; Elizabeth C. Finger; Claire Troakes; Safa Al-Sarraj; Clifton L. Dalgard; Bruce L. Miller; Harro Seelaar; Neill R. Graff-Radford; Bradley F. Boeve; Ian Ra Mackenzie; John C. van Swieten; William W. Seeley; Kristel Sleegers; Dennis W. Dickson; Joanna M. Biernacka; Rosa Rademakers

doi:10.1038/s41467-025-59216-0

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 Gj van Rooij, Merel O. Mol, Ging Yuek R. Hsiung, Caroline Graff, Linn Öijerstedt, Manuela NeumannYan Asmann, Shannon K. McDonnell, Saurabh Baheti, Keith A. Josephs, Jennifer L. Whitwell, Kevin F. Bieniek, Leah Forsberg, Hilary Heuer, Argentina Lario Lago, Ethan G. Geier, Jennifer S. Yokoyama, Alexis P. Oddi, Margaret Flanagan, Qinwen Mao, John R. Hodges, John B. Kwok, Kimiko Domoto-Reilly, Matthis Synofzik, Carlo Wilke, Chiadi Onyike, Bradford C. Dickerson, Bret M. Evers, Brittany N. Dugger, David G. Munoz, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Eun Ran Suh, Tamar Gefen, Changiz Geula, Sandra Weintraub, 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, Nilufer Ertekin-Taner, David S. Knopman, Ronald C. Petersen, Leonard Petrucelli, Ryan J. Uitti, Zbigniew K. Wszolek, 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 P. Vonsattel, Oscar L. Lopez, Julia Kofler, Charles L. White, Marla Gearing, Jonathan Glass, Jonathan D. Rohrer, David J. Irwin, Edward B. Lee, Vivianna Van Deerlin, Rudolph Castellani, Marsel M. Mesulam, Maria C. Tartaglia, Elizabeth C. Finger, Claire Troakes, Safa Al-Sarraj, Clifton L. Dalgard, Bruce L. Miller, Harro Seelaar, Neill R. Graff-Radford, Bradley F. Boeve, Ian Ra Mackenzie, John C. van Swieten, William W. Seeley, Kristel Sleegers, Dennis W. Dickson, Joanna M. Biernacka, Rosa Rademakers

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	3914
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59216-0
State	Published - Dec 2025
Externally published	Yes

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10.1038/s41467-025-59216-0

Cite this

Pottier, C., Küçükali, F., Baker, M., Batzler, A., Jenkins, G. D., van Blitterswijk, M., Vicente, C. T., De Coster, W., Wynants, S., Van de Walle, P., Ross, O. A., Murray, M. E., Faura, J., Haggarty, S. J., van Rooij, J. G., Mol, M. O., Hsiung, G. Y. R., Graff, C., Öijerstedt, L., ... Rademakers, R. (2025). Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing. Nature Communications, 16(1), Article 3914. https://doi.org/10.1038/s41467-025-59216-0

@article{a4050f7db7d54f60915b60ad86533bf0,

title = "Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing",

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.",

author = "Cyril Pottier and Fahri K{\"u}{\c c}{\"u}kali and Matt Baker and Anthony Batzler and Jenkins, {Gregory D.} and {van Blitterswijk}, Marka and Vicente, {Cristina T.} and {De Coster}, Wouter and Sarah Wynants and {Van de Walle}, Pieter and Ross, {Owen A.} and Murray, {Melissa E.} and J{\'u}lia Faura and Haggarty, {Stephen J.} and {van Rooij}, {Jeroen Gj} and Mol, {Merel O.} and Hsiung, {Ging Yuek R.} and Caroline Graff and Linn {\"O}ijerstedt and Manuela Neumann and Yan Asmann and McDonnell, {Shannon K.} and Saurabh Baheti and Josephs, {Keith A.} and Whitwell, {Jennifer L.} and Bieniek, {Kevin F.} and Leah Forsberg and Hilary Heuer and Lago, {Argentina Lario} and Geier, {Ethan G.} and Yokoyama, {Jennifer S.} and Oddi, {Alexis P.} and Margaret Flanagan and Qinwen Mao and Hodges, {John R.} and Kwok, {John B.} and Kimiko Domoto-Reilly and Matthis Synofzik and Carlo Wilke and Chiadi Onyike and Dickerson, {Bradford C.} and Evers, {Bret M.} and Dugger, {Brittany N.} and Munoz, {David G.} and Julia Keith and Lorne Zinman and Ekaterina Rogaeva and Suh, {Eun Ran} and Tamar Gefen and Changiz Geula and Sandra Weintraub and Janine Diehl-Schmid and Farlow, {Martin R.} and Dieter Edbauer and Woodruff, {Bryan K.} and Caselli, {Richard J.} and {Donker Kaat}, {Laura L.} and Huey, {Edward D.} and Reiman, {Eric M.} and Simon Mead and Andrew King and Sigrun Roeber and Nana, {Alissa L.} and Nilufer Ertekin-Taner and Knopman, {David S.} and Petersen, {Ronald C.} and Leonard Petrucelli and Uitti, {Ryan J.} and Wszolek, {Zbigniew K.} and Ramos, {Eliana Marisa} and Grinberg, {Lea T.} and Tempini, {Maria Luisa Gorno} and Rosen, {Howard J.} and Salvatore Spina and Olivier Piguet and Murray Grossman and Trojanowski, {John Q.} and Keene, {C. Dirk} and Jin, {Lee Way} and Johannes Prudlo and Geschwind, {Daniel H.} and Rissman, {Robert A.} and Carlos Cruchaga and Bernardino Ghetti and Halliday, {Glenda M.} and Beach, {Thomas G.} and Serrano, {Geidy E.} and Thomas Arzberger and Jochen Herms and Boxer, {Adam L.} and Honig, {Lawrence S.} and Vonsattel, {Jean P.} and Lopez, {Oscar L.} and Julia Kofler and White, {Charles L.} and Marla Gearing and Jonathan Glass and Rohrer, {Jonathan D.} and Irwin, {David J.} and Lee, {Edward B.} and {Van Deerlin}, Vivianna and Rudolph Castellani and Mesulam, {Marsel M.} and Tartaglia, {Maria C.} and Finger, {Elizabeth C.} and Claire Troakes and Safa Al-Sarraj and Dalgard, {Clifton L.} and Miller, {Bruce L.} and Harro Seelaar and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Mackenzie, {Ian Ra} and {van Swieten}, {John C.} and Seeley, {William W.} and Kristel Sleegers and Dickson, {Dennis W.} and Biernacka, {Joanna M.} and Rosa Rademakers",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-59216-0",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

number = "1",

}

Pottier, C, Küçükali, F, Baker, M, Batzler, A, Jenkins, GD, van Blitterswijk, M, Vicente, CT, De Coster, W, Wynants, S, Van de Walle, P, Ross, OA, Murray, ME, Faura, J, Haggarty, SJ, van Rooij, JG, Mol, MO, Hsiung, GYR, Graff, C, Öijerstedt, L, Neumann, M, Asmann, Y, McDonnell, SK, Baheti, S, Josephs, KA, Whitwell, JL, Bieniek, KF, Forsberg, L, Heuer, H, Lago, AL, Geier, EG, Yokoyama, JS, Oddi, AP, Flanagan, M, Mao, Q, Hodges, JR, Kwok, JB, Domoto-Reilly, K, Synofzik, M, Wilke, C, Onyike, C, Dickerson, BC, Evers, BM, Dugger, BN, Munoz, DG, Keith, J, Zinman, L, Rogaeva, E, Suh, ER, Gefen, T, Geula, C, Weintraub, S, Diehl-Schmid, J, Farlow, MR, Edbauer, D, Woodruff, BK, Caselli, RJ, Donker Kaat, LL, Huey, ED, Reiman, EM, Mead, S, King, A, Roeber, S, Nana, AL, Ertekin-Taner, N, Knopman, DS, Petersen, RC, Petrucelli, L, Uitti, RJ, Wszolek, ZK, Ramos, EM, Grinberg, LT, Tempini, MLG, Rosen, HJ, Spina, S, Piguet, O, Grossman, M, Trojanowski, JQ, Keene, CD, Jin, LW, Prudlo, J, Geschwind, DH, Rissman, RA, Cruchaga, C, Ghetti, B, Halliday, GM, Beach, TG, Serrano, GE, Arzberger, T, Herms, J, Boxer, AL, Honig, LS, Vonsattel, JP, Lopez, OL, Kofler, J, White, CL, Gearing, M, Glass, J, Rohrer, JD, Irwin, DJ, Lee, EB, Van Deerlin, V, Castellani, R, Mesulam, MM, Tartaglia, MC, Finger, EC, Troakes, C, Al-Sarraj, S, Dalgard, CL, Miller, BL, Seelaar, H, Graff-Radford, NR, Boeve, BF, Mackenzie, IR, van Swieten, JC, Seeley, WW, Sleegers, K, Dickson, DW, Biernacka, JM & Rademakers, R 2025, 'Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing', Nature Communications, vol. 16, no. 1, 3914. https://doi.org/10.1038/s41467-025-59216-0

TY - JOUR

T1 - Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing

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, Eun Ran

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

PY - 2025/12

Y1 - 2025/12

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=105004247793&partnerID=8YFLogxK

U2 - 10.1038/s41467-025-59216-0

DO - 10.1038/s41467-025-59216-0

M3 - Article

C2 - 40280976

AN - SCOPUS:105004247793

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3914

ER -