TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers

N. Finch, Minerva M Carrasquillo, M. Baker, N. J. Rutherford, G. Coppola, M. Dejesus-Hernandez, R. Crook, T. Hunter, R. Ghidoni, L. Benussi, Juliana Crook, E. Finger, K. J. Hantanpaa, A. M. Karydas, P. Sengdy, J. Gonzalez, W. W. Seeley, N. Johnson, T. G. Beach, M. MesulamG. Forloni, A. Kertesz, David S Knopman, R. Uitti, C. L. White, Richard John Caselli, C. Lippa, E. H. Bigio, Zbigniew K Wszolek, G. Binetti, I. R. MacKenzie, B. L. Miller, Bradley F Boeve, Steven G Younkin, Dennis W Dickson, Ronald Carl Petersen, Neill R Graff Radford, D. H. Geschwind, Rosa V Rademakers

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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 languageEnglish (US)
Pages (from-to)467-474
Number of pages8
JournalNeurology
Volume76
Issue number5
DOIs
StatePublished - Feb 1 2011

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Frontotemporal Lobar Degeneration
Penetrance
Single Nucleotide Polymorphism
Mutation
Messenger RNA
DNA-Binding Proteins
Homozygote
Case-Control Studies
Alleles
Genotype

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, Minerva M; Baker, M.; Rutherford, N. J.; Coppola, G.; Dejesus-Hernandez, M.; Crook, R.; Hunter, T.; Ghidoni, R.; Benussi, L.; Crook, Juliana; 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, David S; Uitti, R.; White, C. L.; Caselli, Richard John; Lippa, C.; Bigio, E. H.; Wszolek, Zbigniew K; Binetti, G.; MacKenzie, I. R.; Miller, B. L.; Boeve, Bradley F; Younkin, Steven G; Dickson, Dennis W; Petersen, Ronald Carl; Graff Radford, Neill R; Geschwind, D. H.; Rademakers, Rosa V.

In: Neurology, Vol. 76, No. 5, 01.02.2011, p. 467-474.

Research output: Contribution to journalArticle

Finch, N, Carrasquillo, MM, Baker, M, Rutherford, NJ, Coppola, G, Dejesus-Hernandez, M, Crook, R, Hunter, T, Ghidoni, R, Benussi, L, Crook, J, Finger, E, Hantanpaa, KJ, Karydas, AM, Sengdy, P, Gonzalez, J, Seeley, WW, Johnson, N, Beach, TG, Mesulam, M, Forloni, G, Kertesz, A, Knopman, DS, Uitti, R, White, CL, Caselli, RJ, Lippa, C, Bigio, EH, Wszolek, ZK, Binetti, G, MacKenzie, IR, Miller, BL, Boeve, BF, Younkin, SG, Dickson, DW, Petersen, RC, Graff Radford, NR, Geschwind, DH & Rademakers, RV 2011, 'TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers', Neurology, vol. 76, no. 5, pp. 467-474. https://doi.org/10.1212/WNL.0b013e31820a0e3b
Finch, N. ; Carrasquillo, Minerva M ; Baker, M. ; Rutherford, N. J. ; Coppola, G. ; Dejesus-Hernandez, M. ; Crook, R. ; Hunter, T. ; Ghidoni, R. ; Benussi, L. ; Crook, Juliana ; 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, David S ; Uitti, R. ; White, C. L. ; Caselli, Richard John ; Lippa, C. ; Bigio, E. H. ; Wszolek, Zbigniew K ; Binetti, G. ; MacKenzie, I. R. ; Miller, B. L. ; Boeve, Bradley F ; Younkin, Steven G ; Dickson, Dennis W ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Geschwind, D. H. ; Rademakers, Rosa V. / TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. In: Neurology. 2011 ; Vol. 76, No. 5. pp. 467-474.
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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, {Minerva 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 Juliana 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, {David S} and R. Uitti and White, {C. L.} and Caselli, {Richard John} and C. Lippa and Bigio, {E. H.} and Wszolek, {Zbigniew K} and G. Binetti and MacKenzie, {I. R.} and Miller, {B. L.} and Boeve, {Bradley F} and Younkin, {Steven G} and Dickson, {Dennis W} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Geschwind, {D. H.} and Rademakers, {Rosa V}",
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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, Minerva 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, Juliana

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, David S

AU - Uitti, R.

AU - White, C. L.

AU - Caselli, Richard John

AU - Lippa, C.

AU - Bigio, E. H.

AU - Wszolek, Zbigniew K

AU - Binetti, G.

AU - MacKenzie, I. R.

AU - Miller, B. L.

AU - Boeve, Bradley F

AU - Younkin, Steven G

AU - Dickson, Dennis W

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Geschwind, D. H.

AU - Rademakers, Rosa V

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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