Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk

Neurobiol Aging. 2022 Feb:110:122-131. doi: 10.1016/j.neurobiolaging.2021.09.009. Epub 2021 Sep 15.

Abstract

Despite advances, the roles of genetic variants from the APOE-harboring 19q13.32 region in Alzheimer's disease (AD) remain controversial. We leverage a comprehensive approach to gain insights into a more homogeneous genetic architecture of AD in this region. We use a sample of 2,673 AD-affected and 16,246 unaffected subjects from 4 studies and validate our main findings in the landmark Alzheimer's Disease Genetics Consortium cohort (3,662 AD-cases and 1,541 controls). We report the remarkably high excesses of the AD risk for carriers of the ε4 allele who also carry minor alleles of rs2075650 (TOMM40) and rs12721046 (APOC1) polymorphisms compared to carriers of their major alleles. The exceptionally high 4.37-fold (p=1.34 × 10-3) excess was particularly identified for the minor allele homozygotes. The beneficial and adverse variants were significantly depleted and enriched, respectively, in the AD-affected families. This study provides compelling evidence for the definitive roles of the APOE-TOMM40-APOC1 variants in the AD risk.

Keywords: Alzheimer's disease; Apolipoprotein E polymorphism; Haplotypes; Linkage disequilibrium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Alleles
  • Alzheimer Disease / genetics*
  • Apolipoprotein C-I / genetics*
  • Apolipoproteins E / genetics*
  • Cohort Studies
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Mitochondrial Precursor Protein Import Complex Proteins / genetics*
  • Polymorphism, Genetic / genetics*
  • Risk

Substances

  • APOC1 protein, human
  • ApoE protein, human
  • Apolipoprotein C-I
  • Apolipoproteins E
  • Mitochondrial Precursor Protein Import Complex Proteins
  • TOMM40 protein, human