ArticleActa neuropathologica2019
Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.
Registry-linked trialOpen access · greenAbstract read
In one paragraph
Article in Acta neuropathologica, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02372773 (Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects), which is not on this map. Cited by 88 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
88citing papers in PubMed, 1 pooled it
7.6field-weighted citation impact, top 2% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects
Who cites it
88 citing papers in PubMed, 1 synthesis or guideline pooled it, 128 citations in OpenAlex.
- Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis.Scientific data · 2021Pooled it
- A new era of genome-wide association studies in the field of Alzheimer's disease and overlapping co-pathologies: lessons learned from a neuropathology-centered approach.Acta neuropathologica · 2026Review
- TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.Biochemical Society transactions · 2026Review
- Genotype epigenome phenotype integration reveals peripheral immune contributions to type I bipolar disorder.Nature communications · 2026Article
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- The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review.Neurology. Genetics · 2026Article
- A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.Nature genetics · 2026Article
- TDP-43 proteinopathies and neurodegeneration: insights from Caenorhabditis elegans models.The FEBS journal · 2026Review
- CARDBiomedBench: a benchmark for evaluating the performance of large language models in biomedical research.The Lancet. Digital health · 2026Review
- Lysosomal escape and TMEM106B fibrillar core determine TDP-43 seeding outcomes.bioRxiv : the preprint server for biology · 2025Article
- Generation of Induced Pluripotent Stem Cells and Neuroepithelial Stem Cells from a Family with the Pathogenic Variant p.Q337X in Progranulin.International journal of molecular sciences · 2025Article
- Genetic testing of common and rare variants in dementia patients from a memory clinic : Dementia-related genetic testing in memory clinic.Alzheimer's research & therapy · 2025Article
- Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes.Molecular neurodegeneration · 2025Article
- DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal Lobar degeneration genetic risk-associated loci.Acta neuropathologica communications · 2025Article
- UNISOM: Unified Somatic Calling and Machine Learning-based Classification Enhance the Discovery of CHIP.Genomics, proteomics & bioinformatics · 2025Article
- DNA methylation as a contributor to dysregulation ofbioRxiv : the preprint server for biology · 2025Article
- Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.Nature communications · 2025Article
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- Drug repurposing in amyotrophic lateral sclerosis (ALS).Expert opinion on drug discovery · 2025Review
- Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies.PloS one · 2025Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
105 authors at 20 institutions in 7 countries.
Cyril PottierDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Yingxue RenDepartment of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Ralph B PerkersonDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Matt BakerDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Gregory D JenkinsDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Marka van BlitterswijkDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Mariely DeJesus-HernandezDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Jeroen G J van RooijDepartment of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Melissa E MurrayDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Elizabeth ChristopherDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Shannon K McDonnellDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Zachary FogartyDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Anthony BatzlerDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Shulan TianDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Cristina T VicenteDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Billie MatchettDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Anna M KarydasDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Ging-Yuek Robin HsiungDivision of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
Harro SeelaarDepartment of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Merel O MolDepartment of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Elizabeth C FingerDepartment of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 2E2, Canada.
Caroline GraffDivision of Neurogeriatrics, Department NVS, Karolinska Institutet, Visionsgatan 4, J10:20, 171 64, Solna, Sweden.
Linn ÖijerstedtDivision of Neurogeriatrics, Department NVS, Karolinska Institutet, Visionsgatan 4, J10:20, 171 64, Solna, Sweden.
Manuela NeumannGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Peter HeutinkGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Matthis SynofzikGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Carlo WilkeGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Johannes PrudloGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Patrizia RizzuGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Javier Simon-SanchezGerman Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
Dieter EdbauerGerman Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str 17, 81377, Munich, Germany.
Sigrun RoeberCenter for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Straße 23, 81377, Munich, Germany.
Janine Diehl-SchmidDepartment of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
Bret M EversDivision of Neuropathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9073, USA.
Andrew KingLondon Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
M Marsel MesulamMesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, 60611, USA.
Sandra WeintraubMesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, 60611, USA.
Changiz GeulaMesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, 60611, USA.
Kevin F BieniekDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Leonard PetrucelliDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Geoffrey L AhernDepartment of Neurology, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ, 85724-5023, USA.
Eric M ReimanBanner Alzheimer's Institute, Phoenix, AZ, 85006, USA.
Bryan K WoodruffDepartment of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
Richard J CaselliDepartment of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
Edward D HueyDepartments of Psychiatry and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th St P&S Box 16, New York, NY, 10032, USA.
Martin R FarlowIndiana University School of Medicine, 355 West 16th Street, GH 4700 Neurology, Indianapolis, IN, 46202, USA.
Jordan GrafmanDepartment of Physical Medicine and Rehabilitation, Neurology, Cognitive Neurology and Alzheimer's Center, Department of Psychiatry, Feinberg School of Medicine, Northwestern University, 355 E Erie Street, Chicago, IL, 60611-5146, USA.
Simon MeadMRC Prion Unit at University College London, Institute of Prion Diseases, London, UK.
Lea T GrinbergDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Salvatore SpinaDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Murray GrossmanPenn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
David J IrwinPenn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Edward B LeeCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
EunRan SuhCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Julie SnowdenCerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford, UK.
David MannDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, UK.
Nilufer Ertekin-TanerDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Ryan J UittiDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Zbigniew K WszolekDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Keith A JosephsDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Joseph E ParisiDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
David S KnopmanDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C PetersenDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
John R HodgesCentral Clinical School and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
Olivier PiguetSchool of Psychology and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
Ethan G GeierDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Jennifer S YokoyamaDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Robert A RissmanDepartment of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
Ekaterina RogaevaKrembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Av, 4th Floor - 4KD481, Toronto, ON, M5T 0S8, Canada.
Julia KeithSunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada.
Lorne ZinmanSunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada.
Maria Carmela TartagliaKrembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Av, 4th Floor - 4KD481, Toronto, ON, M5T 0S8, Canada.
Nigel J CairnsDepartment of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA.
Carlos CruchagaDepartment of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA.
Bernardino GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MS A138, Indianapolis, IN, 46202, USA.
Julia KoflerDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Oscar L LopezDepartment of Neurology, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ, 85724-5023, USA.
Thomas G BeachCivin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, 85351, USA.
Thomas ArzbergerGerman Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str 17, 81377, Munich, Germany.
Jochen HermsGerman Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str 17, 81377, Munich, Germany.
Lawrence S HonigDepartment of Neurology, Taub Institute, and GH Sergievsky Center, Columbia University Irving Medical Center, 630 West 168th St (P&S Unit 16), New York, NY, 10032, USA.
Jean Paul VonsattelDepartment of Pathology and Taub Institute, Columbia University Irving Medical Center, 630 West 168th St, New York, NY, 10032, USA.
Glenda M HallidayCentral Clinical School and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
John B KwokCentral Clinical School and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
Charles L WhiteDivision of Neuropathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9073, USA.
Marla GearingDepartment of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
Jonathan GlassDepartment of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
Sara RollinsonDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Stuart Pickering-BrownDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Jonathan D RohrerDementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
John Q TrojanowskiCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Vivianna Van DeerlinCenter for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Eileen H BigioMesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, 60611, USA.
Claire TroakesLondon Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
Safa Al-SarrajLondon Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
Yan AsmannDepartment of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
Bruce L MillerDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Neill R Graff-RadfordDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Bradley F BoeveDepartment of Neurology, Mayo Clinic, Rochester, MN, USA.
William W SeeleyDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
Ian R A MackenzieDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
John C van SwietenDepartment of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Joanna M BiernackaDepartment of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Rosa RademakersDepartment of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Rademakers.rosa@mayo.edu.
Mayo Clinic in Florida · USMayo Clinic in Arizona · USUniversity of Pennsylvania · USGerman Center for Neurodegenerative Diseases · DENorthwestern University · USErasmus MC · NLThe University of Sydney · AUUniversity Memory and Aging Center · USHertie Institute for Clinical Brain Research · DEUniversity of California, San Francisco · USColumbia University Irving Medical Center · USEmory University · USIndiana University School of MedicineKarolinska Institutet · SEKing's College London · GBSalford Royal Hospital · GBSunnybrook Health Science Centre · CAThe University of Texas Southwestern Medical Center · USUniversity of Arizona · USUniversity of British Columbia · CA
Funding
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MSmartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI Tammie Lee Smith Benzinger · 1985 to 2026
$69.5MTDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2MVIRUS-INDUCED BRAIN PATHOLOGYP50AG005131 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BREWER, JAMES B · 1985 to 2018
$55.4MWASHINGTON UNIVERSITY ALZHEIMERS DISEASE RESEARCH CENTERP50AG005681 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 1985 to 2019
$52.1MSUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6MSatellite Diagnostic and Treatment Clinic CoreP50AG008702 · NIA · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI DE JAGER, PHILIP L · 1989 to 2019
$46.3MTREATMENT OF DEPRESSION IN ALZHEIMER'S DISEASEP50AG005133 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BECKER, JAMES T. · 1985 to 2019
$43.0MResearch Education ComponentP30AG010133 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI SAYKIN, ANDREW J · 1991 to 2020
$37.3MTransgenic Mouse Models of Tau PathologiesP01AG017586 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LEE, VIRGINIA M · 2000 to 2021
$37.3MTHE PGRN/TDP-43 AXIS IN ALZHEIMER?S DISEASE AND NEURODEGENERATIONP50AG016574 · NIA · MAYO CLINIC ROCHESTER · PI BU, GUOJUN · 1999 to 2018
$36.9MUPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI XIE, SHARON XIANGWEN · 1991 to 2020
$35.1MBLRD VA I01 BX003040Medical Research Council G0701441Medical Research Council MC_UU_00024/1Medical Research Council MR/J009482/1Medical Research Council MR/L016397/1Medical Research Council MR/M008525/1Medical Research Council MR/M023664/1NIA NIH HHS K01 AG049152NIA NIH HHS K08 AG052648NIA NIH HHS K24 AG045333NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG025688NIA NIH HHS R01 AG037491NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG051848NIA NIH HHS R01 AG061796NIA NIH HHS RF1 AG051504NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG045390NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG052943NIA NIH HHS U01 AG058922NIA NIH HHS U24 AG021886NIDCD NIH HHS R01 DC008552NINDS NIH HHS P01 NS084974NINDS NIH HHS P30 NS055077NINDS NIH HHS P50 NS072187NINDS NIH HHS R01 NS076837NINDS NIH HHS R01 NS080820NINDS NIH HHS R01 NS085770NINDS NIH HHS R35 NS097261NINDS NIH HHS U24 NS072026NINDS NIH HHS U24 NS095871NINDS NIH HHS U54 NS092089NINDS NIH HHS UG3 NS103870NINDS NIH HHS UH3 NS103870
Abstract
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
Indexed as
AgedDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA Repeat ExpansionFemaleFrontal LobeFrontotemporal Lobar DegenerationGenetic Predisposition to DiseaseGenome-Wide Association StudyHLA-DQ AntigensHumansIntracellular Signaling Peptides and ProteinsLoss of Function MutationMaleMiddle AgedNerve Tissue ProteinsPotassium ChannelsDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDPP6 protein, humanGRN protein, humanHLA-DQA2 antigenHLA-DQ AntigensIntracellular Signaling Peptides and ProteinsLINC03041 protein, humanNerve Tissue ProteinsPotassium ChannelsProgranulinsProteinsProtein Serine-Threonine KinasesRNA, MessengerTBK1 protein, humanUNC13B protein, humanDPP6HLAImmunityTBK1UNC13AWhole-genome sequencing FTLD-TDP
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NCT02372773ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.