GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.

J Gerontol A Biol Sci Med Sci
Authors
Keywords
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.

Year of Publication
2015
Journal
J Gerontol A Biol Sci Med Sci
Volume
70
Issue
1
Pages
110-8
Date Published
2015 Jan
ISSN
1758-535X
URL
DOI
10.1093/gerona/glu166
PubMed ID
25199915
PubMed Central ID
PMC4296168
Links
Grant list
N01HC55222 / HC / NHLBI NIH HHS / United States
U01 AR45632 / AR / NIAMS NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
U19 AG023122 / AG / NIA NIH HHS / United States
R01 AR35582 / AR / NIAMS NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
UL1 RR024140 / RR / NCRR NIH HHS / United States
263 MD 821336 / MD / NIMHD NIH HHS / United States
U01 AR45647 / AR / NIAMS NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
R01 AR/AG 41398 / AG / NIA NIH HHS / United States
U01 AR45614 / AR / NIAMS NIH HHS / United States
R01 AG027576 / AG / NIA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
U01 AR45654 / AR / NIAMS NIH HHS / United States
RC2ARO58973 / RC / CCR NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
R01 AG005407 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
U01 AG023749 / AG / NIA NIH HHS / United States
R01AG30146 / AG / NIA NIH HHS / United States
U01-AG027810 / AG / NIA NIH HHS / United States
RC2 AG036495 / AG / NIA NIH HHS / United States
R01 AR35583 / AR / NIAMS NIH HHS / United States
U01 AG023755 / AG / NIA NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
U01AG009740 / AG / NIA NIH HHS / United States
U01 AR45583 / AR / NIAMS NIH HHS / United States
HHSN268200800007C / PHS HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
R01 AG005394 / AG / NIA NIH HHS / United States
R01-AR051124 / AR / NIAMS NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
U01 AR45580 / AR / NIAMS NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
HHSN268201200036C / PHS HHS / United States
R01 AR35584 / AR / NIAMS NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
1R01AG028321 / AG / NIA NIH HHS / United States
1R01HL092577 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
U19-AG023122 / AG / NIA NIH HHS / United States
R01AG29451 / AG / NIA NIH HHS / United States
263 MD 9164 / MD / NIMHD NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
R01 AG027574 / AG / NIA NIH HHS / United States
U01-AG023755 / AG / NIA NIH HHS / United States
U01 AG18197 / AG / NIA NIH HHS / United States
U01 AR066160 / AR / NIAMS NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States