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TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort

Julie van der Zee, Tim Van Langenhove, Gernot Kleinberger, Kristel Sleegers, Sebastiaan Engelborghs, Rik Vandenberghe, Patrick Santens UGent, Marleen Van Den Broeck, Geert Joris and Jolien Brys, et al. (2011) BRAIN. 134(3). p.808-815
abstract
In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders-Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95% confidence interval 0.61-0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders-Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
TMEM106B, frontotemporal lobar degeneration, genetic association, risk factor, LINKAGE ANALYSIS, MUTATIONS, DEMENTIA, TOOL, SEGREGATION, CHMP2B, TAU
journal title
BRAIN
Brain
volume
134
issue
3
pages
808 - 815
Web of Science type
Article
Web of Science id
000287745100016
JCR category
CLINICAL NEUROLOGY
JCR impact factor
9.457 (2011)
JCR rank
5/190 (2011)
JCR quartile
1 (2011)
ISSN
0006-8950
DOI
10.1093/brain/awr007
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2016878
handle
http://hdl.handle.net/1854/LU-2016878
date created
2012-02-02 16:23:46
date last changed
2012-02-03 11:19:22
@article{2016878,
  abstract     = {In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders-Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95\% confidence interval 0.61-0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50\% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders-Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis.},
  author       = {van der Zee, Julie and Van Langenhove, Tim and Kleinberger, Gernot and Sleegers, Kristel and Engelborghs, Sebastiaan  and Vandenberghe, Rik and Santens, Patrick and Van Den Broeck, Marleen and Joris, Geert and Brys, Jolien and Mattheijssens, Maria and Peeters, Karin and Cras, Patrick and De Deyn, Peter P and Cruts, Marc and Van Broeckhoven, Christine},
  issn         = {0006-8950},
  journal      = {BRAIN},
  keyword      = {TMEM106B,frontotemporal lobar degeneration,genetic association,risk factor,LINKAGE ANALYSIS,MUTATIONS,DEMENTIA,TOOL,SEGREGATION,CHMP2B,TAU},
  language     = {eng},
  number       = {3},
  pages        = {808--815},
  title        = {TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort},
  url          = {http://dx.doi.org/10.1093/brain/awr007},
  volume       = {134},
  year         = {2011},
}

Chicago
van der Zee, Julie, Tim Van Langenhove, Gernot Kleinberger, Kristel Sleegers, Sebastiaan Engelborghs, Rik Vandenberghe, Patrick Santens, et al. 2011. “TMEM106B Is Associated with Frontotemporal Lobar Degeneration in a Clinically Diagnosed Patient Cohort.” Brain 134 (3): 808–815.
APA
van der Zee, J., Van Langenhove, T., Kleinberger, G., Sleegers, K., Engelborghs, S., Vandenberghe, R., Santens, P., et al. (2011). TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. BRAIN, 134(3), 808–815.
Vancouver
1.
van der Zee J, Van Langenhove T, Kleinberger G, Sleegers K, Engelborghs S, Vandenberghe R, et al. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. BRAIN. 2011;134(3):808–15.
MLA
van der Zee, Julie, Tim Van Langenhove, Gernot Kleinberger, et al. “TMEM106B Is Associated with Frontotemporal Lobar Degeneration in a Clinically Diagnosed Patient Cohort.” BRAIN 134.3 (2011): 808–815. Print.