title: TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers.
abstract: OBJECTIVE
  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, p(allelic) = 0.036). However, the most significant association with risk of FTLD was observed in the subgroup of GRN mutation carriers compared to controls (corrected p(allelic) = 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 p(recessive) = 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(-5)) and controls (r = -0.49, p = 2.2 × 10(-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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: N
authors.initials: N
authors.lastname: Finch
authors.forename: M M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: M
authors.initials: M
authors.lastname: Baker
authors.forename: N J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: G
authors.initials: G
authors.lastname: Coppola
authors.forename: M
authors.initials: M
authors.lastname: Dejesus-Hernandez
authors.forename: R
authors.initials: R
authors.lastname: Crook
authors.forename: T
authors.initials: T
authors.lastname: Hunter
authors.forename: R
authors.initials: R
authors.lastname: Ghidoni
authors.forename: L
authors.initials: L
authors.lastname: Benussi
authors.forename: J
authors.initials: J
authors.lastname: Crook
authors.forename: E
authors.initials: E
authors.lastname: Finger
authors.forename: K J
authors.initials: KJ
authors.lastname: Hantanpaa
authors.forename: A M
authors.initials: AM
authors.lastname: Karydas
authors.forename: P
authors.initials: P
authors.lastname: Sengdy
authors.forename: J
authors.initials: J
authors.lastname: Gonzalez
authors.forename: W W
authors.initials: WW
authors.lastname: Seeley
authors.forename: N
authors.initials: N
authors.lastname: Johnson
authors.forename: T G
authors.initials: TG
authors.lastname: Beach
authors.forename: M
authors.initials: M
authors.lastname: Mesulam
authors.forename: G
authors.initials: G
authors.lastname: Forloni
authors.forename: A
authors.initials: A
authors.lastname: Kertesz
authors.forename: D S
authors.initials: DS
authors.lastname: Knopman
authors.forename: R
authors.initials: R
authors.lastname: Uitti
authors.forename: C L
authors.initials: CL
authors.lastname: White
authors.forename: R
authors.initials: R
authors.lastname: Caselli
authors.forename: C
authors.initials: C
authors.lastname: Lippa
authors.forename: E H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Z K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: G
authors.initials: G
authors.lastname: Binetti
authors.forename: I R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: B L
authors.initials: BL
authors.lastname: Miller
authors.forename: B F
authors.initials: BF
authors.lastname: Boeve
authors.forename: S G
authors.initials: SG
authors.lastname: Younkin
authors.forename: D W
authors.initials: DW
authors.lastname: Dickson
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
authors.forename: N R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: D H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: R
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D056726:Genetic Association Studies; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics*; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000077153:Progranulins; D011498:Protein Precursors / Q000097:blood / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D011498:Protein Precursors; C556915:TMEM106B protein, human