Abstract
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, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 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 precessive = 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) and controls (r = -0.49, p = 2.2 × 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.
Original language | English (US) |
---|---|
Pages (from-to) | 467-474 |
Number of pages | 8 |
Journal | Neurology |
Volume | 76 |
Issue number | 5 |
DOIs | |
State | Published - Feb 1 2011 |
ASJC Scopus subject areas
- Clinical Neurology
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TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. / Finch, N.; Carrasquillo, M. M.; Baker, M. et al.
In: Neurology, Vol. 76, No. 5, 01.02.2011, p. 467-474.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers
AU - Finch, N.
AU - Carrasquillo, M. M.
AU - Baker, M.
AU - Rutherford, N. J.
AU - Coppola, G.
AU - Dejesus-Hernandez, M.
AU - Crook, R.
AU - Hunter, T.
AU - Ghidoni, R.
AU - Benussi, L.
AU - Crook, J.
AU - Finger, E.
AU - Hantanpaa, K. J.
AU - Karydas, A. M.
AU - Sengdy, P.
AU - Gonzalez, J.
AU - Seeley, W. W.
AU - Johnson, N.
AU - Beach, T. G.
AU - Mesulam, M.
AU - Forloni, G.
AU - Kertesz, A.
AU - Knopman, D. S.
AU - Uitti, R.
AU - White, C. L.
AU - Caselli, R.
AU - Lippa, C.
AU - Bigio, E. H.
AU - Wszolek, Z. K.
AU - Binetti, G.
AU - MacKenzie, I. R.
AU - Miller, B. L.
AU - Boeve, B. F.
AU - Younkin, S. G.
AU - Dickson, D. W.
AU - Petersen, R. C.
AU - Graff-Radford, N. R.
AU - Geschwind, D. H.
AU - Rademakers, R.
N1 - Funding Information: Supported by the NIH [P50 AG16574 (Mayo ADRC R.C.P. PI; to R.R., B.F.B., N.R.G.-R., D.W.D., S.G.Y.), U01 AG06576 (Mayo Alzheimer's Disease Patient Registry: R.C.P. PI) ; R01 NS065782 (to R.R.), R01 AG18023 (to N.R.G.-R., S.G.Y.), RC1AG0356101 (to G.C.), R01AG026938 (to G.C., D.H.G.), AG19724 and AG023501 (to B.L.M., D.H.G.), AG1657303 (to B.L.M., W.W.S.), AG25711 (to D.W.D.), AG17216 (to D.W.D., Z.K.W.), AG03949 (to D.W.D.), AG13854 (to M.M., E.H.B.), DC008552 (to M.M.)] and the Consortium for Frontotemporal Dementia Research (to R.R., D.H.G., G.C., W.W.S., B.L.M.). The work of T.G.B. at the Banner Sun Health Research Institute is supported by the NIA [P30 AG19610 (Arizona Alzheimer's Disease Core Center)], the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05–901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. Z.K.W. is partially supported by the NIH [RC2NS070276, NS40256, NS057567, NS070276] , the Mayo Clinic Florida Research Committee CR program, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. K.J.H. and C.L.W. were supported by the NIH [5P30AG012300] , the Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, and the McCune Foundation. I.R.M. was supported by the Canadian Institutes of Health Research Operating (#74580) and the Pacific Alzheimer's Disease Research Foundation. R.G., L.B., and G.B. are supported by grants Fondazione CARIPLO 2009–2633, FIRB 2006 “Gen-Etica”; Progetto Regione Lombardia, Delibera N°VIII/008724 . This project was also supported by the Robert and Clarice Smith Postdoctoral Fellowship (M.M.C.); Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (R.C.P., D.W.D., N.R.G.-R.; S.G.Y.); and the Palumbo Professorship in Alzheimer's Disease Research (S.G.Y.). Funding Information: N. Finch reports no disclosures. Dr. Carrasquillo received research support from the Robert and Clarice Smith Postdoctoral Fellowship. M. Baker may accrue revenue on patents re: Methods and materials for detecting and treating dementia. N.J. Rutherford, M. DeJesus-Hernandez, R. Crook, and T. Hunter report no disclosures. Dr. Ghidoni serves as Managing Editor for Frontiers in Bioscience and as an Associate Editor for the Journal of Alzheimer's Disease and the International Journal of Clinical and Experimental Medicine and receives research support from Fondazione CARIPLO and Progetto Regione Lombardia. Dr. Benussi receives research support from Progetto Regione Lombardia. Dr. Crook receives research support from the NIH. Dr. Finger receives research support from the Lawson Health Research Institute, the University of Western Ontario Academic Development Fund, the Hazel Soper Foundation, and the Alzheimer's Society of London and Middlesex. Dr. Hantanpaa serves as a consultant for Biosite, Inc. and receives research support from the NIH. A.M. Karydas reports no disclosures. P. Sengdy receives salary support from CIHR. Dr. Coppola receives research support from the NIH, the Consortium for Frontotemporal Dementia Research, the Adelson Medical Research Foundation, the Tau Consortium, and the Easton Consortium. J. Gonzalez reports no disclosures. Dr. Seeley receives research support from the NIH, the James S. McDonnell Foundation, and the Consortium for Frontotemporal Dementia Research. Dr. Johnson reports no disclosures. Dr. Beach receives research support from Avid Radiopharmaceuticals, Inc., Bayer Schering Pharma, GE Healthcare, the NIH, the Arizona Department of Health Services, and the Arizona Biomedical Research Commission. Dr. Mesulam serves on the scientific advisory boards for the Cure Alzheimer Fund and the Association on Frontotemporal Dementia; serves on the editorial boards of Brain , Annals of Neurology , Human Brain Mapping , and Journal of Cognitive Neuroscience ; receives royalties from the publication of Principles of Behavioral and Cognitive Neurology (Oxford University Press, 2000); and receives research support from the NIH. Dr. Forloni receives research support from the European Commission. Dr. Kertesz serves on a scientific advisory board for Pfizer Inc.; serves on the editorial boards of Cognitive and Behavioral Neurology and Aphasiology ; receives royalties from the publication of The Western Aphasia Battery (Grune and Stratton, 1982); and has received support from the Lawson Research Institute, the American Neurological Society, and the Whitaker professorship. Dr. Knopman serves as Deputy Editor of Neurology ®; has served on data safety monitoring boards for Sanofi-Aventis, GlaxoSmithKline, and Eli Lilly and Company; is an investigator in clinical trials sponsored by Elan Corporation, Baxter International Inc., and Forest Laboratories, Inc.; and receives research support from the NIH. Dr. Uitti serves as an Associate Editor of Neurology ®; has received research support from Advanced Neuromodulations Systems and the NIH; and his institution receives annual royalties from Lundbeck Inc. from the licensing of the technology related to PARK8/LRRK2. Dr. White serves as a scientific advisor for the Michael J. Fox Foundation for Parkinson's Research and receives research support from the NIH, the Winspear Family Center for Research on the Neuropathology of Alzheimer's Disease, and the McCune Foundation. Dr. Caselli serves as Medical Editor for Clinical Neurology News and receives research support from the NIH/NIA and the Arizona Alzheimer's Research Consortium. Dr. Lippa serves on scientific advisory boards for the Association for Frontotemporal Dementias, the Lewy Body Dementia Association, and the Alzheimer's Association (Delaware Valley Chapter); serves as Editor-in-Chief of the American Journal of Alzheimer Disease and Other Disorders and the editorial boards of Neurology ® and Journal of Neuropathology & Experimental Neurology ; and has received research support from UCB, Novartis, Elan Corporation, Janssen, Danone, Potamkin Foundation, and the Newmann Foundation. Dr. Bigio serves on the editorial boards of the Journal of Neuropathology and Experimental Neurology , Acta Neuropathologica , and Brain Pathology . Dr. Wszolek serves as Co-Editor-in-Chief of Parkinsonism and Related Disorders , Regional Editor of the European Journal of Neurology , and on the editorial boards of Neurologia i Neurochirurgia Polska , Advances in Rehabilitation , the Medical Journal of the Rzeszow University , and Clinical and Experimental Medical Letters ; holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease; receives royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2007, 2008, 2009) and the European Journal of Neurology (Wiley-Blackwell, 2007, 2008, 2009); and receives research support from Allergan, Inc., the NIH, the Pacific Alzheimer Research Foundation (Canada), the CIHR, the Mayo Clinic Florida Research Committee CR program, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Dr. Binetti receives research support from FIRB 2006 “Gen-Etica” and Progetto Regione Lombardia. Dr. Mackenzie serves on the editorial boards of Journal of Neuropathology and Experimental Neurology , Neuroinflammation , Clinical Neuropathology , and Neurobiology of Aging ; and receives research support from the CIHR, the Pacific Alzheimer Research Fund, and Michael Smith Foundation for Health Research. Dr. Miller serves on a scientific advisory board for the Alzheimer's Disease Clinical Study, serves as an Editor for Neurocase, and as an Associate Editor of ADAD ; receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge, 2009), Handbook of Neurology (Elsevier, 2009), and The Human Frontal Lobes (Guilford, 2008); serves as a consultant for Lundbeck Inc., Allon Therapeutics, Inc., and Novartis; and receives research support from Novartis, the NIH, and the State of California Alzheimer's Center. Dr. Boeve receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge University Press, 2009) and receives research support from Cephalon, Inc., the NIH, and the Alzheimer's Association. Dr. Younkin has received funding for travel and speaker honoraria from Eisai Inc.; receives royalty payments from Mayo for licensing of Tg2576 mouse model of Alzheimer disease; and receives research support from the NIH and the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program. Dr. Dickson serves on the editorial boards of the American Journal of Pathology , Journal of Neuropathology and Experimental Neurology , Brain Pathology , Neurobiology of Aging , Journal of Neurology, Neurosurgery, and Psychiatry , Annals of Neurology , and Neuropathology ; and receives research support from the NIH. Dr. Petersen serves on scientific advisory boards for Elan Corporation, Wyeth, and GE Healthcare; receives royalties from publishing Mild Cognitive Impairment (Oxford University Press, 2003); and receives research support from the NIH. Dr. Graff-Radford serves on a scientific advisory board for and has received funding for travel from Codman; serves on the editorial boards of The Neurologist and Alzheimer Disease and Therapy ; has a patent pending on the Ab40Ab42 ratio as a predictor of Alzheimer disease; received royalties for an article in UpToDate; and receives research support from Pfizer Inc., Janssen, Elan Corporation, Forest Laboratories, Inc., Medivation, Inc., and the NIH. Dr. Geschwind serves on scientific advisory boards for Autism Speaks, the Alzheimer Research Forum, and the March of Dimes Birth Defects Foundation; serves on the editorial boards of Neuron , Neurogenetics , the Neurobiology of Disease , Current Genomics , Biological Psychiatry , Autism Research , the Encyclopedia of Autism and Related Disorders , and Biomed Central ; may accrue revenue on patents re: Peripheral gene expression biomarkers for autism and full biomarkers in Friedreich's ataxia; and receives research support from the NIH, The Simons Foundation, and the Consortium for Frontotemporal Dementia Research. Dr. Rademakers holds patents re: Methods and materials for detecting and treating dementia; and receives research support from the NIH, the Pacific Alzheimer Research Foundation (Canada), the Association for Frontotemporal Dementia, the Amyotrophic Lateral Sclerosis Association, and CurePSP.
PY - 2011/2/1
Y1 - 2011/2/1
N2 - 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, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 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 precessive = 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) and controls (r = -0.49, p = 2.2 × 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.
AB - 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, pallelic = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected pallelic = 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 precessive = 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) and controls (r = -0.49, p = 2.2 × 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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U2 - 10.1212/WNL.0b013e31820a0e3b
DO - 10.1212/WNL.0b013e31820a0e3b
M3 - Article
C2 - 21178100
AN - SCOPUS:79951494607
VL - 76
SP - 467
EP - 474
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 5
ER -