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

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

doi:10.1111/j.1474-9726.2011.00705.x

Abstract

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.

Highlights

Worldwide human populations have shown an increase in mean life expectancy in the past two centuries (Oeppen & Vaupel, 2002)
A Genome-wide association study (GWAS) was performed in nonagenarian participants from the Leiden Longevity Study (LLS) and middle-aged controls from the Rotterdam Study (RS)
Genotype data for 516,721 SNPs that passed quality control thresholds were analyzed in a comparison of 403 unrelated nonagenarians (94 years on average) and 1670 controls (58 years on average)

Summary

Introduction

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 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

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