GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.
Broer L., Buchman AS., Deelen J., Evans DS., Faul JD., Lunetta KL., Sebastiani P., Smith JA., Smith AV., Tanaka T., Yu L., Arnold AM., Aspelund T., Benjamin EJ., De Jager PL., Eirkisdottir G., Evans DA., Garcia ME., Hofman A., Kaplan RC., Kardia SLR., Kiel DP., Oostra BA., Orwoll ES., Parimi N., Psaty BM., Rivadeneira F., Rotter JI., Seshadri S., Singleton A., Tiemeier H., Uitterlinden AG., Zhao W., Bandinelli S., Bennett DA., Ferrucci L., Gudnason V., Harris TB., Karasik D., Launer LJ., Perls TT., Slagboom PE., Tranah GJ., Weir DR., Newman AB., van Duijn CM., Murabito JM.
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.