. 2025 Apr 25;16(1):3914.

doi: 10.1038/s41467-025-59216-0.

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

Cyril Pottier^{1

2

3

4

5}, Fahri Küçükali^{6

7}, Matt Baker⁸, Anthony Batzler⁹, Gregory D Jenkins⁹, Marka van Blitterswijk⁸, Cristina T Vicente^{6

7}, Wouter De Coster^{6

7}, Sarah Wynants^{6

7}, Pieter Van de Walle^{6

7}, Owen A Ross⁸, Melissa E Murray⁸, Júlia Faura^{6

7}, Stephen J Haggarty¹⁰, Jeroen Gj van Rooij¹¹, Merel O Mol¹¹, Ging-Yuek R Hsiung¹², Caroline Graff^{13

14}, Linn Öijerstedt^{13

14}, Manuela Neumann^{15

16}, Yan Asmann¹⁷, Shannon K McDonnell⁹, Saurabh Baheti⁹, Keith A Josephs¹⁸, Jennifer L Whitwell¹⁹, Kevin F Bieniek^{8

20}, Leah Forsberg¹⁸, Hilary Heuer²¹, Argentina Lario Lago²¹, Ethan G Geier²¹, Jennifer S Yokoyama²¹, Alexis P Oddi²¹, Margaret Flanagan²⁰, Qinwen Mao²², John R Hodges²³, John B Kwok^{24

25}, Kimiko Domoto-Reilly²⁶, Matthis Synofzik^{15

27}, Carlo Wilke^{15

27}, Chiadi Onyike²⁸, Bradford C Dickerson²⁹, Bret M Evers³⁰, Brittany N Dugger³¹, David G Munoz^{32

33}, Julia Keith^{33

34}, Lorne Zinman³⁴, Ekaterina Rogaeva³⁵, EunRan Suh³⁶, Tamar Gefen³⁷, Changiz Geula³⁷, Sandra Weintraub³⁷, Janine Diehl-Schmid^{38

39}, Martin R Farlow⁴⁰, Dieter Edbauer⁴¹, Bryan K Woodruff⁴², Richard J Caselli⁴², Laura L Donker Kaat⁴³, Edward D Huey⁴⁴, Eric M Reiman⁴⁵, Simon Mead⁴⁶, Andrew King^{47

48}, Sigrun Roeber⁴⁹, Alissa L Nana²¹, Nilufer Ertekin-Taner^{8

50}, David S Knopman¹⁸, Ronald C Petersen¹⁸, Leonard Petrucelli⁸, Ryan J Uitti⁵⁰, Zbigniew K Wszolek⁵⁰, Eliana Marisa Ramos⁵¹, Lea T Grinberg²¹, Maria Luisa Gorno Tempini²¹, Howard J Rosen⁵², Salvatore Spina²¹, Olivier Piguet⁵³, Murray Grossman⁵⁴, John Q Trojanowski³⁶, C Dirk Keene⁵⁵, Lee-Way Jin⁵⁶, Johannes Prudlo^{57

58}, Daniel H Geschwind⁵¹, Robert A Rissman⁵⁹, Carlos Cruchaga⁶⁰, Bernardino Ghetti⁶¹, Glenda M Halliday²⁴, Thomas G Beach⁶², Geidy E Serrano⁶², Thomas Arzberger^{49

63}, Jochen Herms^{41

49}, Adam L Boxer²¹, Lawrence S Honig⁶⁴, Jean P Vonsattel⁶⁵, Oscar L Lopez⁶⁶, Julia Kofler⁶⁷, Charles L White 3rd³⁰, Marla Gearing⁶⁸, Jonathan Glass⁶⁸, Jonathan D Rohrer⁶⁹, David J Irwin⁵⁴, Edward B Lee³⁶, Vivianna Van Deerlin³⁶, Rudolph Castellani⁷⁰, Marsel M Mesulam³⁷, Maria C Tartaglia³⁵, Elizabeth C Finger⁷¹, Claire Troakes⁴⁷, Safa Al-Sarraj^{47

72}, Clifton L Dalgard⁷³, Bruce L Miller²¹, Harro Seelaar¹¹, Neill R Graff-Radford⁵⁰, Bradley F Boeve¹⁸, Ian Ra Mackenzie⁷⁴, John C van Swieten¹¹, William W Seeley²¹, Kristel Sleegers^{6

7}, Dennis W Dickson⁸, Joanna M Biernacka^{9

75}, Rosa Rademakers^{76

77

78}

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. cpottier@wustl.edu.
² Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. cpottier@wustl.edu.
³ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. cpottier@wustl.edu.
⁴ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. cpottier@wustl.edu.
⁵ NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA. cpottier@wustl.edu.
⁶ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁷ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹² Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
¹³ Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden.
¹⁴ Unit for Hereditary Dementias, Karolinska University Hospital, Solna, Sweden.
¹⁵ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁶ Department of Neuropathology, University of Tübingen, Tübingen, Germany.
¹⁷ Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
²⁰ University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
²¹ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
²² Department of Pathology, University of Utah, Salt Lake City, UT, USA.
²³ Central Clinical School and Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
²⁴ University of Sydney, Sydney, NSW, Australia.
²⁵ NeuRA, University of New South Wales, Randwick, NSW, Australia.
²⁶ Department of Neurology, University of Washington, Seattle, WA, USA.
²⁷ Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁸ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
²⁹ Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
³⁰ Division of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³¹ Department of Pathology and Laboratory Medicine, University of California, Davis Medical Center, Sacramento, CA, USA.
³² St. Michael's Hospital, Toronto, ON, Canada.
³³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³⁴ Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³⁵ Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada.
³⁶ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, USA.
³⁸ Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany.
³⁹ kbo-Inn-Salzach-Klinikum, Clinical Center for Psychiatry, Psychotherapy, Psychosomatic Medicine, Geriatrics and Neurology, Wasserburg/Inn, Germany.
⁴⁰ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴² Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
⁴³ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
⁴⁴ Department of Psychiatry and Human Behavior, Brown Alpert Medical School, Brown University, Providence, RI, USA.
⁴⁵ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁴⁶ MRC Prion Unit at University College London, Institute of Prion Diseases, London, UK.
⁴⁷ Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴⁸ Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK.
⁴⁹ Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
⁵⁰ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁵¹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵² Department of Pathology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁵³ School of Psychology and Brain and Mind Centre, University of Sydney, Sydney, SWA, Australia.
⁵⁴ Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁵⁵ University of Washington BioRepository and Integrated Neuropathology (BRaIN) lab, Harborview Medical Center, Seattle, WA, USA.
⁵⁶ M.I.N.D. Institute Laboratory, University of California, Davis Medical Center, Sacramento, CA, USA.
⁵⁷ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
⁵⁸ Department of Neurology, Rostock University Medical Center, Rostock, Germany.
⁵⁹ Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, San Diego, CA, USA.
⁶⁰ Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.
⁶¹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶² Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁶³ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
⁶⁴ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
⁶⁵ Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
⁶⁶ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁷ Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁸ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, USA.
⁶⁹ Department of Neurodegenerative Disease, Dementia Research Centre, University College London, Queen Square Institute of Neurology, London, UK.
⁷⁰ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷¹ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
⁷² King's College Hospital NHS Foundation Trust, London, UK.
⁷³ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷⁴ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁷⁵ Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA.
⁷⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. rosa.rademakers@uantwerpen.vib.be.
⁷⁷ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. rosa.rademakers@uantwerpen.vib.be.
⁷⁸ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. rosa.rademakers@uantwerpen.vib.be.

PMID: 40280976
PMCID: PMC12032271
DOI: 10.1038/s41467-025-59216-0

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

Cyril Pottier et al. Nat Commun. 2025.

. 2025 Apr 25;16(1):3914.

doi: 10.1038/s41467-025-59216-0.

Authors

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. cpottier@wustl.edu.
² Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. cpottier@wustl.edu.
³ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. cpottier@wustl.edu.
⁴ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. cpottier@wustl.edu.
⁵ NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA. cpottier@wustl.edu.
⁶ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
⁷ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹² Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
¹³ Division of Neurogeriatrics, Karolinska Institutet, Solna, Sweden.
¹⁴ Unit for Hereditary Dementias, Karolinska University Hospital, Solna, Sweden.
¹⁵ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁶ Department of Neuropathology, University of Tübingen, Tübingen, Germany.
¹⁷ Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
¹⁸ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
²⁰ University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
²¹ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
²² Department of Pathology, University of Utah, Salt Lake City, UT, USA.
²³ Central Clinical School and Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
²⁴ University of Sydney, Sydney, NSW, Australia.
²⁵ NeuRA, University of New South Wales, Randwick, NSW, Australia.
²⁶ Department of Neurology, University of Washington, Seattle, WA, USA.
²⁷ Division Translational Genomics of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁸ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
²⁹ Department of Neurology, Case Western Reserve University, Cleveland, OH, USA.
³⁰ Division of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³¹ Department of Pathology and Laboratory Medicine, University of California, Davis Medical Center, Sacramento, CA, USA.
³² St. Michael's Hospital, Toronto, ON, Canada.
³³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³⁴ Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³⁵ Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada.
³⁶ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, USA.
³⁸ Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany.
³⁹ kbo-Inn-Salzach-Klinikum, Clinical Center for Psychiatry, Psychotherapy, Psychosomatic Medicine, Geriatrics and Neurology, Wasserburg/Inn, Germany.
⁴⁰ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴² Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
⁴³ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
⁴⁴ Department of Psychiatry and Human Behavior, Brown Alpert Medical School, Brown University, Providence, RI, USA.
⁴⁵ Banner Alzheimer's Institute, Phoenix, AZ, USA.
⁴⁶ MRC Prion Unit at University College London, Institute of Prion Diseases, London, UK.
⁴⁷ Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁴⁸ Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK.
⁴⁹ Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Munich, Germany.
⁵⁰ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁵¹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵² Department of Pathology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁵³ School of Psychology and Brain and Mind Centre, University of Sydney, Sydney, SWA, Australia.
⁵⁴ Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁵⁵ University of Washington BioRepository and Integrated Neuropathology (BRaIN) lab, Harborview Medical Center, Seattle, WA, USA.
⁵⁶ M.I.N.D. Institute Laboratory, University of California, Davis Medical Center, Sacramento, CA, USA.
⁵⁷ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
⁵⁸ Department of Neurology, Rostock University Medical Center, Rostock, Germany.
⁵⁹ Alzheimer's Therapeutic Research Institute, Keck School of Medicine of the University of Southern California, San Diego, CA, USA.
⁶⁰ Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA.
⁶¹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶² Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁶³ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
⁶⁴ Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
⁶⁵ Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
⁶⁶ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁷ Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁸ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, USA.
⁶⁹ Department of Neurodegenerative Disease, Dementia Research Centre, University College London, Queen Square Institute of Neurology, London, UK.
⁷⁰ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷¹ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
⁷² King's College Hospital NHS Foundation Trust, London, UK.
⁷³ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷⁴ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁷⁵ Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA.
⁷⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. rosa.rademakers@uantwerpen.vib.be.
⁷⁷ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. rosa.rademakers@uantwerpen.vib.be.
⁷⁸ VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. rosa.rademakers@uantwerpen.vib.be.

PMID: 40280976
PMCID: PMC12032271
DOI: 10.1038/s41467-025-59216-0

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.

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Conflict of interest statement

Competing interests: S.J.H. serves on the scientific advisory board (SAB) of Proximity Therapeutics, Psy Therapeutics, Frequency Therapeutics, Souvien Therapeutics, Sensorium Therapeutics, 4 M Therapeutics, Ilios Therapeutics, Entheos Labs, Alzheimer’s Drug Discovery Foundation, and the Kissick Family Foundation FTD Grant Program, none of whom were involved in the present study. S.J.H. has also received speaking or consulting fees from Amgen, AstraZeneca, Biogen, Merck, Regenacy Pharmaceuticals, Syros Pharmaceuticals, Juvenescence Life, as well as sponsored research or gift funding from AstraZeneca, JW Pharmaceuticals, Lexicon Pharmaceuticals, Vesigen Therapeutics, Compass Pathways, Atai Life Sciences, and Stealth Biotherapeutics. The funders had no role in the design or content of this article. ZKW serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206), Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia), and ONO-2808-03 projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant for Eli Lilly & Company and for NovoGlia, Inc. R.R. and I.R.M. receive royalties from progranulin-related patent. The remaining authors declare no competing interests.

Figures

**Fig. 1. Genome-wide association study on common variants.**
Association studies were performed using logistic regression with allele dosage as the predictor assuming log-additive allele effects adjusted for relevant covariates. Raw two-sided P are reported as −log10(P). A Manhattan plot of the FTLD-TDP All patients versus controls association study (inflation, λ = 1.05). B Manhattan plot of the FTLD-TDP A patients versus controls association study (λ = 1.07). C Manhattan plot of the FTLD-TDP B patients versus controls association study (λ = 1.06). D Manhattan plot of the FTLD-TDP C patients versus controls association study (λ = 1.05). The red-dotted line represents the genome-wide significance level (p = 5 × 10⁻⁸).

**Fig. 2. Gene prioritization results for FTLD-TDP subgroups.**
A visual summary of weighted evidence category scores for the prioritized genes within genome-wide significant loci in related FTLD subtype-specific GWAS summary statistics. Using the gene prioritization strategy in these selected loci, we prioritized a total of 13 genes in 12 genome-wide significant loci at two different confidence levels (10 tier 1 and 3 tier 2 prioritized genes). The leftmost squares, which are colored in red for FTLD-TDP A, in blue for FTLD-TDP B, in lighter green for FTLD-TDP C, and in darker green for FTLD-TDP C* specific analyzes, indicate the locus index numbers for the genome-wide loci. The types of evidence for each category are colored according to the six different domains to which they belonged. Weighted scores for each evidence category are rescaled to a 0–100 scale based on the maximum score a candidate gene can obtain from a category (see Supplementary Data 3). The darker colors represent higher scores in categories, while tier 1 prioritized genes are displayed in dark green, and tier 2 prioritized genes are displayed in light green. Only tier 1 and tier 2 genes are shown for each locus, whereas all candidate genes considered and scored can be found in Supplementary Data 4. MAFs (based on gnomAD v4 non-Finnish European samples) and CADD (v1.7) PHRED scores for rare and/or protein-altering rare variants are labeled in white within the respective squares. eQTL expression QTL, sQTL splicing QTL, mQTL methylation QTL, pQTL protein-expression QTL, haQTL histone acetylation QTL, coloc colocalization, eTWAS expression transcriptome-wide association study, sTWAS splicing transcriptome-wide association study, PWAS proteome-wide association study, Mon Mac monocytes and macrophages, LCL lymphoblastoid cell line, QTLCat the eQTL catalog.

**Fig. 3. Top 5 Gene Ontology terms enriched in FTLD-TDP subgroups.**
Hierarchical GO analysis of biological process terms considering genes in genetic loci prioritized for FTLD-TDP All, FTLD-TDP A, FTLD-TDP B, and FTD-TDP C. Raw two-sided p values are represented.

**Fig. 4. Enrichment of brain regions and cell types in FTLD subgroups.**
A Enrichment of genes in multiple tissues, including 13 brain regions, and based on GTEX data in FTLD subgroups, ADRD, and ALS. Color represents the enrichment coefficient, and size indicates two-sided −log10 (FDR-adjusted Ps) of enrichment obtained by the linear regression model in the MAGMA gene property analysis. B Central nervous system cell type enrichment analyzes in FTLD subgroups, ADRD, and ALS. Color represents the enrichment coefficient, and size indicates two-sided −log10 (FDR-adjusted Ps) of enrichment obtained by the linear regression model in the MAGMA gene property analysis. Excitatory neurons and glial cells are highlighted in blue. Excitatory and inhibitory neurons from the PsychENCODE dataset were labeled based on their transcriptional profile from 1 to 8. Asterisks denote brain regions or cell types enriched with FDR P < 0.05. Cx cortex, Ex* Excitatory neuron, In* inhibitory neurons, Oligo oligodendrocytes, OPCs oligodendrocyte progenitor cells, Astro astrocytes, Endo endothelial cells, Per pericytes.

**Fig. 5. Locus zoom plots for *UNC13A* and *TNIP1* loci.**
A Genetic colocalization between the *UNC13A* locus in FTLD (meta-analysis) and ALS signal. B Genetic colocalization between the *TNIP1* locus in FTLD (meta-analysis) and ALS. C Genetic colocalization between the *TNIP1* locus in FTLD (meta-analysis) and ADRD. For A, B, C, chromosome position is located on the x-axis, and −log10 transformed raw two-sided P is represented on the y-axis. Each dot represents a SNV tested in the dataset for its association with disease status. Purple diamonds are the index SNVs reported. Linkage disequilibrium with index SNV is indicated by r².

**Fig. 6. Rare loss of function and predicted pathogenic variants in proteins associated with FTLD.**
Schematic representation of C3AR1, SMG8, VIPR1, L3MBTL1, and RBPL protein structure (source Uniprot) showing a map of nonsense, splicing, frameshift, and missense rare variants with a REVEL score > 0.75 in patients and controls. Variants identified in patients are colored in orange, and variants identified in controls are colored in blue. n = number of carriers. When no number is indicated, the variant was observed in a single individual. Total number of subjects included in the analyzes was FTLD-TDP A (n = 193), FTLD-TDP B (n = 288), FTLD-TDP C (n = 467), and FTLD-TDP C* (n = 199), and controls (n = 3153).

**Fig. 7. Schematic representation of findings from the International FTLD-TDP WGS phase II.**
Genome-wide significant single variant loci, exome-wide significant genes, enriched gene ontology pathways, and tissues- and cell-types enriched for genome-wide significant risk loci are shown for each FTLD-TDP pathological subtype in rings moving from the center (genome-wide significant single variant loci in FTLD-TDP All) to the outer rings. Orange background shades correspond to FTLD-TDP A findings, green background shades to FTLD-TDP B findings, and blue background shades to FTLD-TDP C findings. Gene names in green font were exome-wide significant using a gene-based approach with common variants, while gene names in red font were exome-wide significant using a gene-based approach with rare variants. In addition to unique associations, some overlap between FTLD-TDP A and B exists (*TBK1*, lysosomal function, and inflammatory response), whereas FTLD-TDP C showed a unique and non-overlapping genetic profile. Note that genetic associations with *LRP1B*, *COL22A1*, *TRPC4,* and *TMEM135* (identified in the FTLD-TDP C* GWAS focused solely on pathologically confirmed FTLD-TDP C patients) are not shown.

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Update of

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.
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 GR, 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 E, 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, Gorno Tempini ML, Rosen HJ, Spina S, Piguet O, Grossman M, Trojanowski JQ, Keene DC, Lee-Way J, 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, Troak… See abstract for full author list ➔ Pottier C, et al. medRxiv [Preprint]. 2024 Jun 25:2024.06.24.24309088. doi: 10.1101/2024.06.24.24309088. medRxiv. 2024. Update in: Nat Commun. 2025 Apr 25;16(1):3914. doi: 10.1038/s41467-025-59216-0. PMID: 38978643 Free PMC article. Updated. Preprint.

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1. Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and its variants. Neurology76, 1006–1014 (2011). - PMC - PubMed
1. Lee, E. B. et al. Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol.134, 65–78 (2017). - PMC - PubMed
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Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing

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

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