title: Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels.
abstract: OBJECTIVE
  To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.
  
  
  METHODS
  Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.
  
  
  METHODS
  Alzheimer's Disease Research Center. Subjects  We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.
  
  
  METHODS
  Age at onset and GRN plasma levels.
  
  
  RESULTS
  The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
  
  
  CONCLUSIONS
  The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.forename: Huei-Hsin
authors.initials: HH
authors.lastname: Chiang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Noah
authors.initials: N
authors.lastname: Spiegel
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Norton
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D019943:Amino Acid Substitution; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012694:Serine; D013912:Threonine; D013997:Time Factors
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; C556915:TMEM106B protein, human; D013912:Threonine; D012694:Serine