Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
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Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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The study identified two lysosomal proteins, GRN and TMEM106B, that are associated with frontotemporal dementia but were also identified in the latest AD risk GWAS.
“We also identified two lysosomal proteins, GRN and TMEM106B80,81, that are associated with frontotemporal dementia (FTD)82,83 but were also identified in the latest AD risk GWAS23.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [82]
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- Authors
- Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L.-S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., Pickering-Brown, S. M., Seelaar, H., Heutink, P., van Swieten, J. C., Murrell, J. R., Ghetti, B., Spina, S., Grafman, J., Hodges, J., Spillantini, M. G., Gilman, S., Lieberman, A. P., Kaye, J. A., Woltjer, R. L., Bigio, E. H., Mesulam, M., al-Sarraj, S., Troakes, C., Rosenberg, R. N., White, C. L., Ferrer, I., Lladó, A., Neumann, M., Kretzschmar, H. A., Hulette, C. M., Welsh-Bohmer, K. A., Miller, B. L., Alzualde, A., de Munain, A. L., McKee, A. C., Gearing, M., Levey, A. I., Lah, J. J., Hardy, J., Rohrer, J. D., Lashley, T., Mackenzie, I. R. A., Feldman, H. H., Hamilton, R. L., Dekosky, S. T., van der Zee, J., Kumar-Singh, S., Van Broeckhoven, C., Mayeux, R., Vonsattel, J. P. G., Troncoso, J. C., Kril, J. J., Kwok, J. B. J., Halliday, G. M., Bird, T. D., Ince, P. G., Shaw, P. J., Cairns, N. J., Morris, J. C., McLean, C. A., DeCarli, C., Ellis, W. G., Freeman, S. H., Frosch, M. P., Growdon, J. H., Perl, D. P., Sano, M., Bennett, D. A., Schneider, J. A., Beach, T. G., Reiman, E. M., Woodruff, B. K., Cummings, J., Vinters, H. V., Miller, C. A., Chui, H. C., Alafuzoff, I., Hartikainen, P., Seilhean, D., Galasko, D., Masliah, E., Cotman, C. W., Tuñón, M. T., Martínez, M. C. C., Munoz, D. G., Carroll, S. L., Marson, D., Riederer, P. F., Bogdanovic, N., Schellenberg, G. D., Hakonarson, H., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Mayo Clinic (US)
- University of Manchester (GB)
- Erasmus MC (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Indiana University School of Medicine (US)
- University of Siena (IT)
- National Institute of Neurological Disorders and Stroke (US)
- Neuroscience Research Australia (AU)
- University of Cambridge (GB)
- University of Michigan (US)
- Oregon Health & Science University (US)
- Northwestern University (US)
- King's College London (GB)
- The University of Texas Southwestern Medical Center (US)
- Hospital Clínic de Barcelona (ES)
- University Hospital Zurich (CH)
- Institut für Neuropathologie (DE)
- Duke University (US)
- Duke Medical Center (US)
- University of California, San Francisco (US)
- Biogipuzkoa Health Research Institute (ES)
- Boston University (US)
- Emory University (US)
- UCL Queen Square Institute of Neurology (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- University of British Columbia (CA)
- University of Pittsburgh (US)
- University of Virginia Medical Center (US)
- Columbia University (US)
- Johns Hopkins University (US)
- The University of Sydney (AU)
- UNSW Sydney (AU)
- University of Washington (US)
- University of Sheffield (GB)
- Washington University in St. Louis (US)
- The Alfred Hospital (AU)
- University of California, Davis (US)
- Harvard University (US)
- Icahn School of Medicine at Mount Sinai (US)
- James J. Peters VA Medical Center (US)
- Rush University Medical Center (US)
- Banner Sun Health Research Institute (US)
- Translational Genomics Research Institute (US)
- Mayo Clinic in Arizona (US)
- University of California, Los Angeles (US)
- University of Southern California (US)
- Uppsala University (SE)
- Assistance Publique – Hôpitaux de Paris (FR)
- University of California San Diego (US)
- University of California, Irvine (US)
- University of Alabama at Birmingham (US)
- University of Würzburg (DE)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Trojanowski, John Q
- ORCID
- Wang, Li-San
- Dickson, Dennis W
- Rademakers, Rosa
- Boeve, Bradley F
- Grossman, Murray
- Arnold, Steven E
- Mann, David M A
- Pickering-Brown, Stuart M
- Seelaar, Harro
- Heutink, Peter
- Murrell, Jill R
- Ghetti, Bernardino
- Spina, Salvatore
- Grafman, Jordan
- Hodges, John
- Spillantini, Maria Grazia
- Lieberman, Andrew P
- Kaye, Jeffrey A
- Woltjer, Randall L
- Bigio, Eileen H
- Mesulam, Marsel
- Troakes, Claire
- White, Charles L
- Lladó, Albert
- Neumann, Manuela
- Welsh-Bohmer, Kathleen A
- Miller, Bruce L
- Alzualde, Ainhoa
- McKee, Ann C
- Gearing, Marla
- Levey, Allan I
- Lah, James J
- Hardy, John
- Rohrer, Jonathan D
- Lashley, Tammaryn
- Mackenzie, Ian R A
- Feldman, Howard H
- Hamilton, Ronald L
- Dekosky, Steven T
- Mayeux, Richard
- Troncoso, Juan C
- Kril, Jillian J
- Kwok, John B J
- Halliday, Glenda M
- Bird, Thomas D
- Ince, Paul G
- Shaw, Pamela J
- Cairns, Nigel J
- Morris, John C
- McLean, Catriona Ann
- DeCarli, Charles
- Frosch, Matthew P
- Perl, Daniel P
- Sano, Mary
- Bennett, David A
- Schneider, Julie A
- Beach, Thomas G
- Reiman, Eric M
- Woodruff, Bryan K
- Cummings, Jeffrey
- Vinters, Harry V
- Chui, Helena C
- Alafuzoff, Irina
- Hartikainen, Päivi
- Seilhean, Danielle
- Galasko, Douglas
- Masliah, Eliezer
- Cotman, Carl W
- Carroll, Steven L
- Marson, Daniel
- Riederer, Peter F
- Schellenberg, Gerard D
- Hakonarson, Hakon
- Trojanowski, John Q
- Lee, Virginia M-Y
- Venue
- Nature Genetics
- Published
- 2010-02-14
- Volume
- 42
- Issue
- 3
- Pages
- 234-239
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2828525
- OpenAlex
- W2163955717
- Cited by
- 579
- References
- 7
- Citations by year
- 2026: 33 · 2025: 41 · 2024: 53 · 2023: 40 · 2022: 34 · 2021: 37 · 2020: 29 · 2019: 18 · 2018: 34 · 2017: 34 · 2016: 27 · 2015: 31 · 2014: 37 · 2013: 31 · 2012: 42
- FWCI
- 23.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (05-901, 211002)
- Arizona Department of Health Services (05-901, 211002)
- Wellcome Trust (089701, 75480)
- Alzheimer's Society
- Alzheimer's Research Trust
- Deutsche Forschungsgemeinschaft (NS044233, AG5131, AG10124)
- Bundesministerium für Bildung und Forschung (01GI0505)
- Belgian Federal Science Policy Office
- Eusko Jaurlaritza
- Fonds Wetenschappelijk Onderzoek (P6/43)
- Universitat de Barcelona
- Hersenstichting
- Stichting Dioraphte
- Vlaamse regering
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Instituut Born-Bunge
- Arizona Biomedical Research Commission (05–901, 211002)
- National Institutes of Health (AG5131, 05-901, AG 10 124, 5p50ns038372-10, 211002, AG05133, AG03949, AG‐18440, AG05142, NS53488, NS044233, AG005131, AG 17586, AG008017, AG010129, AG13854, AG005681, AG08702, AG05138, AG19610, AG 05146, AG08671, AG10161, NS038372, AG025688, AG 03991, AG02219, NS15655, AG16574, AG005136, AG13846, AG05134)
- Canadian Institutes of Health Research (75480, C06-01)
- Medical Research Council
- National Health and Medical Research Council (211002)
- National Institute on Aging (AG08702, AG010133, AG15116, P30AG010129, P30AG010133, AG 05-133, AG033101, AG13854, AG 10161, AG 08671, AG 13846, AG03991, AG-02219, P30AG012300, AG 025688, R37AG018440, AG03949, AG-005136, R01AG018440, AG 05142, AG008017, P50AG005133, AG 16573, P30AG028377, AG 16574, AG 05138, P50AG005131, AG-5131, AG-19610, P50AG005138, P50AG016570, P01AG003949, P30AG010124, P50AG016573, AG 16570, R01AG015116, AG 16582, P01AG017586, AG010129, AG 18440, AG17586, P30AG008017, AG-10124, P30AG010161, AG005131, AG028377, P50AG016582, P50AG008702, K08AG033101, P50AG005681, P50AG005142, P50AG008671, P30AG019610, P50AG005146, P01AG003991, P30AG013846, P50AG005136, P50AG005134, P30AG013854, AG 05146, P50AG025688, AG 12300, AG 05134, P01AG002219, AG005681, P01AG019724, P50AG016574)
- National Institute of Neurological Disorders and Stroke (NS53488, P01NS044233, P50-NS-038372, NS-44266, NS-044233, NS-15655, NS 038372, P01NS015655, P50NS053488, R01NS065782, R01NS044266)
- National Center for Research Resources (UL1RR025741)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal lobar degeneration, FTLD-TDP, TDP-43 inclusions, TMEM106B, genetic susceptibility, common genetic variants, linkage disequilibrium, GRN mutations, progranulin, brain gene expression, early-onset dementia
- MeSH terms
- Progranulins, Inclusion Bodies, Chromosomes, Human, Pair 7, DNA-Binding Proteins, Gene Frequency, Genotype, Humans, Membrane Proteins, Linkage Disequilibrium, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Intercellular Signaling Peptides and Proteins, Genome-Wide Association Study, Frontotemporal Lobar Degeneration
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