title: TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort.
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.
authors.affiliation: Neurodegenerative Brain Disease Group, VIB Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Tim
authors.initials: T
authors.lastname: Van Langenhove
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Geert
authors.initials: G
authors.lastname: Joris
authors.forename: Jolien
authors.initials: J
authors.lastname: Brys
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C556915:TMEM106B protein, human