GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy

J Gerontol A Biol Sci Med Sci. 2015 Jan;70(1):110-8. doi: 10.1093/gerona/glu166. Epub 2014 Sep 8.

Abstract

Background: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

Methods: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

Results: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

Conclusions: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

Keywords: APOE.; FOXO3; GWAS; Longevity.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoproteins E / genetics*
  • Cell Adhesion Molecules / genetics
  • Cohort Studies
  • Female
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics*
  • Genome-Wide Association Study
  • Humans
  • Longevity / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Receptors, Kainic Acid / genetics

Substances

  • Apolipoproteins E
  • CADM2 protein, human
  • Cell Adhesion Molecules
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Gluk2 kainate receptor
  • Receptors, Kainic Acid

Grant support