TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
Open accessAbstract
OBJECTIVES: To determine whether TMEM106B single nucleotide polymorphisms (SNPs) are associated with frontotemporal lobar degeneration (FTLD) in patients with and without mutations in progranulin (GRN) and to determine whether TMEM106B modulates GRN expression. METHODS: We performed a case-control study of 3 SNPs in TMEM106B in 482 patients with clinical and 80 patients with pathologic FTLD-TAR DNA-binding protein 43 without GRN mutations, 78 patients with FTLD with GRN mutations, and 822 controls. Association analysis of TMEM106B with GRN plasma levels was performed in 1,013 controls and TMEM106B and GRN mRNA expression levels were correlated in peripheral blood samples from 33 patients with FTLD and 150 controls. RESULTS: In our complete FTLD patient cohort, nominal significance was identified for 2 TMEM106B SNPs (top SNP rs1990622, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 0.0009), where there was a highly significant decrease in the frequency of homozygote carriers of the minor alleles of all TMEM106B SNPs (top SNP rs1990622, CC genotype frequency 2.6% vs 19.1%, corrected p(recessive) = 0.009). We further identified a significant association of TMEM106B SNPs with plasma GRN levels in controls (top SNP rs1990622, corrected p = 0.002) and in peripheral blood samples a highly significant correlation was observed between TMEM106B and GRN mRNA expression in patients with FTLD (r = -0.63, p = 7.7 × 10(-5)) and controls (r = -0.49, p = 2.2 × 10(-10)). CONCLUSIONS: In our study, TMEM106B SNPs significantly reduced the disease penetrance in patients with GRN mutations, potentially by modulating GRN levels. These findings hold promise for the development of future protective therapies for FTLD.
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- Authors
- Finch, N., Carrasquillo, M. M., Baker, M., Rutherford, N. J., Coppola, G., DeJesus-Hernandez, M., Crook, R., Hunter, T., Ghidoni, R., Benussi, L., Crook, J., Finger, E., Hantanpaa, K. J., Karydas, A. M., Sengdy, P., Gonzalez, J., Seeley, W. W., Johnson, N., Beach, T. G., Mesulam, M., Forloni, G., Kertesz, A., Knopman, D. S., Uitti, R., White, C. L., Caselli, R., Lippa, C., Bigio, E. H., Wszolek, Z. K., Binetti, G., Mackenzie, I. R., Miller, B. L., Boeve, B. F., Younkin, S. G., Dickson, D. W., Petersen, R. C., Graff-Radford, N. R., Geschwind, D. H., & Rademakers, R.
- Affiliations
- Mayo Clinic (US)
- From the Departments of Neuroscience (N.F., M.M.C., M.B., N.J.R., M.D.-H., R.C., T.H., J.C., J.G., S.G.Y., D.W.D., R.R.) and Neurology (R.U., Z.K.W., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Department of Neurology (G.C., D.H.G.), The David Geffen School of Medicine at University of California, Los Angeles; Proteomics Unit and NeuroBioGen Lab-Memory Clinic (R.G., L.B., G.B.), IRCCS “Centro S. Giovanni di Dio-Fatebenefratelli,” Brescia, Italy; Department of Clinical Neurological Sciences (E.F., A.K...
- Western University (CA)
- ORCID
- Carrasquillo, M.M.
- Baker, M.
- Coppola, G.
- Crook, R.
- Hunter, T.
- Ghidoni, R.
- Benussi, L.
- Crook, J.
- Finger, E.
- Seeley, W.W.
- Johnson, N.
- Beach, T.G.
- Mesulam, M.
- Forloni, G.
- Kertesz, A.
- Knopman, D.S.
- Uitti, R.
- White, C.L.
- Caselli, R.
- Lippa, C.
- Bigio, E.H.
- Binetti, G.
- Mackenzie, I.R.
- Miller, B.L.
- Boeve, B.F.
- Dickson, D.W.
- Petersen, R.C.
- Geschwind, D.H.
- Rademakers, R.
- Venue
- Neurology
- Published
- 2011-02
- Volume
- 76
- Issue
- 5
- Pages
- 467-474
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3034409
- OpenAlex
- W2098219309
- Cited by
- 243
- References
- 26
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 15 · 2023: 19 · 2022: 8 · 2021: 19 · 2020: 20 · 2019: 12 · 2018: 16 · 2017: 15 · 2016: 21 · 2015: 11 · 2014: 24 · 2013: 15 · 2012: 16
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Speaks
- Michael J. Fox Foundation for Parkinson's Research (05-901, 211002, P30 AG19610)
- Mayo Clinic (05-901, P50 AG16574, P30 AG19610, 211002)
- Simons Foundation
- March of Dimes Foundation
- James S. McDonnell Foundation
- Alzheimer's Association
- ALS Association
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Sanofi
- Baxter International
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Arizona Department of Health Services (P30 AG19610, R01 AG18023, 05-901, 211002, Contract 211002)
- Danone
- CurePSP
- Lawson Health Research Institute
- Demensförbundet
- Alzheimer's Society
- Lewy Body Dementia Association
- Michael Smith Health Research BC
- University of Cambridge
- University of Oxford
- European Commission
- Fondazione Cariplo
- Elan
- Eisai
- Regione Lombardia
- H. Lundbeck A/S
- Fondation pour la Recherche sur Alzheimer
- Arizona Biomedical Research Commission (P30 AG19610, 05–901, Contracts 4001, 0011, 05‐901 and 1001, 4001, 0011, 05-901, and 1001, 211002)
- National Institutes of Health (05-901, 5rc2ns070276-02, 211002, AG03949, AG023501, NS40256, AG13854, AG19610, AG19724, NS070276, AG16574, AG17216)
- Forest Laboratories
- Allergan
- Avid Radiopharmaceuticals
- Tau Consortium
- Canadian Institutes of Health Research (74580)
- National Institute on Aging (211002, P30-AG-19610, AG13854, U01 AG 06576, P50‐AG16574, P30AG012300, AG03949, R01AG018023, AG 16574, AG-19610, P01AG003949, AG 25711, R01-AG18023, AG-19724, RC1AG0356101, AG 17216, P50AG025711, AG023501, P30AG019610, 05-901, P01AG017216, P30AG013854, R01AG026938, AG1657303, P01AG019724, P50AG023501, P50AG016574)
- National Institute on Deafness and Other Communication Disorders (R01DC008552, DC008552)
- National Institute of Neurological Disorders and Stroke (P01NS040256, RC2-NS070276, NS057567, NS 40256, P50NS040256, R01NS057567, R01NS065782, NS070276)
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- TMEM106B, progranulin, GRN mutations, frontotemporal lobar degeneration, disease penetrance, single nucleotide polymorphisms, genetic risk factors, protective therapy, TDP-43 pathology
- MeSH terms
- Progranulins, Adult, Aged, Aged, 80 and over, Female, Genetic Carrier Screening, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Nerve Tissue Proteins, Protein Precursors, Cohort Studies, Case-Control Studies, Penetrance, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Intercellular Signaling Peptides and Proteins, Genetic Association Studies, Frontotemporal Lobar Degeneration
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