Comprehensive search for Alzheimer disease susceptibility loci in the APOE region

Arch Neurol. 2012 Oct;69(10):1270-9. doi: 10.1001/archneurol.2012.2052.

Abstract

Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).

Design: Conditional logistic regression models and survival analysis.

Setting: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.

Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.

Main outcome measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.

Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.

Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / mortality
  • Apolipoproteins E / genetics*
  • Chromosomes, Human, Pair 19 / genetics
  • Cohort Studies
  • DNA Repeat Expansion / genetics
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Logistic Models
  • Male
  • Membrane Transport Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Survival Analysis

Substances

  • Apolipoproteins E
  • Membrane Transport Proteins
  • TOMM40 protein, human

Grant support