title: Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease.
abstract: BACKGROUND
  Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene.
  
  
  OBJECTIVE
  To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
  
  
  METHODS
  We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue.
  
  
  METHODS
  Alzheimer's Disease Research Center.
  
  
  METHODS
  Research volunteers who were cognitively normal or had Alzheimer disease.
  
  
  METHODS
  Disease status and age at onset.
  
  
  RESULTS
  We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or β-amyloid 42 levels or TOMM40 or APOE gene expression.
  
  
  CONCLUSIONS
  Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.forename: Petra
authors.initials: P
authors.lastname: Nowotny
authors.forename: John S K
authors.initials: JS
authors.lastname: Kauwe
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.forename: Kevin
authors.initials: K
authors.lastname: Mayo
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Anthony
authors.initials: A
authors.lastname: Hinrichs
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D053318:Apolipoprotein E3 / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011071:Poly T / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D053318:Apolipoprotein E3; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human; D011071:Poly T