@article{bcec07c828604489a0badb17170da025,
title = "TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers",
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.",
author = "N. Finch and Carrasquillo, {M. M.} and M. Baker and Rutherford, {N. J.} and G. Coppola and M. Dejesus-Hernandez and R. Crook and T. Hunter and R. Ghidoni and L. Benussi and J. Crook and E. Finger and Hantanpaa, {K. J.} and Karydas, {A. M.} and P. Sengdy and J. Gonzalez and Seeley, {W. W.} and N. Johnson and Beach, {T. G.} and M. Mesulam and G. Forloni and A. Kertesz and Knopman, {D. S.} and R. Uitti and White, {C. L.} and R. Caselli and C. Lippa and Bigio, {E. H.} and Wszolek, {Z. K.} and G. Binetti and MacKenzie, {I. R.} and Miller, {B. L.} and Boeve, {B. F.} and Younkin, {S. G.} and Dickson, {D. W.} and Petersen, {R. C.} and Graff-Radford, {N. R.} and Geschwind, {D. H.} and R. Rademakers",
note = "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.). ",
year = "2011",
month = feb,
day = "1",
doi = "10.1212/WNL.0b013e31820a0e3b",
language = "English (US)",
volume = "76",
pages = "467--474",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "5",
}