Contents lists available at ScienceDirect Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev    

Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals

Almut Nebel a,1, Rabea Kleindorp a,1, Amke Caliebe b,1, Michael Nothnagel b, He´le`ne Blanche´ c, Olaf Junge b, Michael Wittig a, David Ellinghaus a, Friederike Flachsbart a, Heinz-Erich Wichmann d,e,f, Thomas Meitinger d,g, Susanna Nikolaus h, Andre Franke a, Michael Krawczak b,i, Mark Lathrop c, Stefan Schreiber a,h,i,*

aInstitute of Clinical Molecular Biology, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany bInstitute of Medical Informatics and Statistics, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, cFondation Jean Dausset-Centre du Polymorphisme Humain (CEPH), Paris, France dInstitute of Epidemiology, Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health, Neuherberg, Germany eInstitute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians University, Munich, Germany fKlinikum Grosshadern, Munich, Germany gInstitute of Human Genetics, Technical University Munich, Munich, Germany hClinic for Internal Medicine I, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany iPopgen Biobank, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany

aInstitute of Clinical Molecular Biology, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany bInstitute of Medical Informatics and Statistics, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel,

gInstitute of Human Genetics, Technical University Munich, Munich, Germany hClinic for Internal Medicine I, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany iPopgen Biobank, at the Christian Albrechts University and the University Hospital Schleswig-Holstein, Kiel, Germany

conducted a case–control genome-wide association study (GWAS) of human longevity, comparing autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the gene, achieved genome-wide significance (allele-based P = 1.8 Bx 1 10(cid:3)10). However, logistic analysis revealed that this association, which was replicated in an independent German is fully explicable by linkage disequilibrium with the APOE allele e4, the only variant hitherto as a major genetic determinant of survival into old age. Our GWAS failed to identify any autosomal susceptibility genes. One explanation for this lack of success in our study would be provide only limited statistical power for a polygenicphenotype with loci ofsmalleffect such human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE–longevity thus strengthening the conclusion that this locus is a very, if not the most, important genetic influencing longevity.

 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

that predisposes to both Alzheimer’s and cardiovascular diseases (Corder et al., 1993; Panza et al., 2004). APOE e4 is the only variant with a reportedly large adverse effect upon survival at advanced age (Scha¨chter et al., 1994), and this association has been replicated in several populations (Christensen et al., 2006). Variation in the human forkhead box O3A gene (FOXO3A), in contrast, has been found to be associated with the ability to live long, an effect corroborated by studies in Japanese, German, Italian, US-American, Jewish, Chinese and Danish populations (Anselmi et al., 2009; Flachsbart et al., 2009; Li et al., 2009; Pawlikowska et al., 2009; Soerensen et al., 2010; Willcox et al., 2008). More recently, we have identified exonuclease 1 (EXO1) as a potential novel longevity gene (Nebel et al., 2009). All three genes were detected through candidate-gene approaches.

Approximately 25–30% of the variation in adult lifespan is attributable to genetic factors that become more important with increasing age and exert their strongest effects in nonagenarians and centenarians (Go¨gele et al., 2010; Hjelmborg et al., 2006). As yet, however, only a few genetic variants have been found consistently to influence longevity. The first to be discovered was the e4 allele of the apolipoprotein E (APOE) gene, a mortality factor

* Corresponding author at: Institute of Clinical Molecular Biology, Christian- Albrechts-University, Schittenhelmstrasse 12, 24105 Kiel, Germany. Tel.: +49 431 597 2350; fax: +49 431 597 2196.

A few genome-wide association studies (GWAS) for the longevity phenotype have been reported so far. In 2007, a

0047-6374/$ – see front matter © 2 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2011.06.008