Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited

J Deelen, M Beekman, HW Uh, Q Helmer, Maris Kuningas, L Christiansen, D Kremer, R van der Breggen, HED Suchiman, N Lakenberg, EB van den Akker, WM Passtoors, Henning Tiemeier, D van Heemst, AJ de Craen, Fernando Rivadeneira, EJ de Geus, M Perola, FJ van der Ouderaa, DA GunnDI Boomsma, André Uitterlinden, K Christensen, Cornelia Duijn, BT (Bastiaan) Heijmans, JJ Houwing-Duistermaat, RGJ Westendorp, PE (Eline) Slagboom

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By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P < 1 x 10(-4)) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR = 0.71 (95% CI 0.65-0.77), P = 3.39 x 10(-17)]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE epsilon 4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE epsilon 4 allele. No other major longevity locus was found.
Original languageUndefined/Unknown
Pages (from-to)686-698
Number of pages13
JournalAging Cell
Issue number4
Publication statusPublished - 2011

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