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

Date Published: August , 2011

Publisher: Blackwell Publishing Ltd

Author(s): Joris Deelen, Marian Beekman, Hae-Won Uh, Quinta Helmer, Maris Kuningas, Lene Christiansen, Dennis Kremer, Ruud van der Breggen, H Eka D Suchiman, Nico Lakenberg, Erik B van den Akker, Willemijn M Passtoors, Henning Tiemeier, Diana van Heemst, Anton J de Craen, Fernando Rivadeneira, Eco J de Geus, Markus Perola, Frans J van der Ouderaa, David A Gunn, Dorret I Boomsma, André G Uitterlinden, Kaare Christensen, Cornelia M van Duijn, Bastiaan T Heijmans, Jeanine J Houwing-Duistermaat, Rudi G J Westendorp, P Eline Slagboom.


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 × 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 × 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 ε4 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 ε4 allele. No other major longevity locus was found.

Partial Text

Worldwide human populations have shown an increase in mean life expectancy in the past two centuries (Oeppen & Vaupel, 2002). This is mainly because of environmental factors such as improved hygiene, nutrition, and health care. The large variation in healthy lifespan among the elderly has prompted research into the determinants of aging and lifespan regulation. The genetic contribution to human lifespan variation was estimated at 25–30% in twin studies (Gudmundsson et al., 2000; Skytthe et al., 2003; Hjelmborg et al., 2006). The most prominent genetic influence is observed in families in which the capacity to attain a long lifespan clusters (Perls et al., 2000; Schoenmaker et al., 2006). Exceptional longevity can be reached with a low degree of age-related disability (Christensen et al., 2008; Terry et al., 2008), raising the question whether protective mechanisms against disease exist in long-lived subjects.

To identify common SNPs contributing to longevity, GWAS analysis of 403 nonagenarian cases and 1670 population controls was performed. Of the 62 top associating SNPs, 58 were tested in a meta-analysis of 4149 nonagenarian cases and 7582 younger controls and we identified one SNP, rs2075650, that associated significantly with survival into old age (P = 3.39 × 10−17). Carriers of the minor allele had a 29% decreased probability of reaching 90 years on average. Although cases and controls originate from different generations, we concluded that there was no substructure to an extent that would affect the observations.




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