Alzheimer's disease: rare variants with large effect sizes

Curr Opin Genet Dev. 2015 Aug;33:49-55. doi: 10.1016/j.gde.2015.07.008. Epub 2015 Aug 22.


Recent advances in sequencing technology and novel genotyping arrays (focused on low-frequency and coding variants) have made it possible to identify novel coding variants with large effect sizes and also novel genes (TREM2, PLD3, UNC5C, and AKAP9) associated with Alzheimer's disease (AD) risk. The major advantages of these studies over the classic genome-wide association studies (GWAS) include the identification of the functional variant and the gene-driven association. In addition to the large effect size, these studies make it possible to model these variants and genes using cell and animal systems. On the other hand, the underlying population-variability of these very low allele frequency variants poses a great challenge to replicating results. Studies that include very large datasets (>10,000 cases and controls) and combine sequencing and genotyping approaches will lead to the identification of novel genes for Alzheimer's disease.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Gene Frequency / genetics
  • Genetic Variation*
  • Genetics, Population*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Polymorphism, Single Nucleotide