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 |
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ASJC Scopus subject areas
- Clinical Neurology
Cite this
TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. / 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.
In: Neurology, Vol. 76, No. 5, 01.02.2011, p. 467-474.Research output: Contribution to journal › Article
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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.
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.
UR - http://www.scopus.com/inward/record.url?scp=79951494607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79951494607&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e31820a0e3b
DO - 10.1212/WNL.0b013e31820a0e3b
M3 - Article
VL - 76
SP - 467
EP - 474
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 5
ER -