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

Helsinki, Finland

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. Andre´ G. Uitterlinden,

,

,

Kaare Christensen,

,

Cornelia M. van Duijn,

,

Bastiaan T. Heijmans,

Jeanine J. Houwing-Duistermaat,

Rudi G. J. Westendorp

,

and P. Eline Slagboom

,

14Unilever Discover, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK

Summary

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 popula- tion controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonage- narian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 priori- tized 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 apolipo- protein E (APOE) gene. Although there was only moder- ate linkage disequilibrium between rs2075650 and the ApoE e4 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 pheno- types 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 dele- terious effects of the ApoE e4 allele. No other major lon-

de Fernando Eco J de Geus,

Markus Perola,

Frans J. van der Ouderaa,

,

David A. Gunn,

Dorret I. Andre´ G. Uitterlinden,

,

,

Kaare Christensen,

,

Cornelia M. van Duijn,

,

Bastiaan T. Heijmans,

Jeanine J. Houwing-Duistermaat,

Rudi G. J. Westendorp

,

and P. Eline Slagboom

,

Section of Molecular Epidemiology, Leiden University Medical Center, PO Box

,

RC Leiden, The Netherlands

Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, PO Box

,

RC Leiden, The Netherlands

Section of Medical Statistics, Leiden University Medical Center, PO Box

,

RC Leiden, The Netherlands

Department of Epidemiology, Erasmus Medical Center, PO Box

,

CE Rotterdam, The Netherlands

Department of Epidemiology, University of Southern Denmark, J.B. Winsløws Vej

, DK-

Odense C, Denmark

The Danish Aging Research Center, Institute of Public Health- Epidemiology, J.B. Winsløws Vej

B, st. tv, DK-

Odense C, Denmark

Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, DK-

Odense C, Denmark

Department of Mediamatics, Delft Bioinformatics Lab, Delft University of Technology, PO Box

,

GA Delft, The Netherlands

Department of Child and Adolescent Psychiatry, Erasmus Center and Sophia Children’s Hospital, PO Box

,

CE Rotterdam, The Netherlands

Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box

,

RC Leiden, The Netherlands

Department of Internal Medicine, Erasmus Medical Center, PO Box

,

CE Rotterdam, The Netherlands

Department of Biological Psychology, VU University Van der Boechorststraat

,

BT Amsterdam, The

Key words: aging; apolipoprotein E; genetics; genome- wide association study; human; longevity.

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 large variation in healthy lifespan among the elderly has prompted research into the determinants of aging and lifespan regulation. The

Accepted for publication 11 March

nonagenarians siblings have a lower prevalence of type 2 diabe- tes, myocardial infarction and hypertension (Westendorp et al., 2009), a beneficial glucose, lipid, and thyroid metabolism, and a preservation of insulin sensitivity with age (Rozing et al., 2009, 2010a,b; Vaarhorst et al., 2011; Wijsman et al., 2011). Hence, in middle age, these families display beneficial metabolic profiles.

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 mecha- nisms against disease exist in long-lived subjects.