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genome-wide association study of aging

Stefan Waltera,b,1, Gil Atzmonc,d,e,1, Ellen W. Demerathf,1, Melissa E. Garciag,1, Robert C. Kaplanh,1, Meena Kumarii,1, Kathryn L. Lunettaj,1, Yuri Milaneschik,1, Toshiko Tanakak,1, Gregory J. Tranahl,1, Uwe Völkerm,1, Lei Yun,1, Alice Arnoldo, J. Benjaminp,q, Reiner Biffarr, Aron S. Buchmann, Eric Boerwinkles, David Coupert, Philip L. De Jageru, Denis A. Evansv, Tamara B. Harrisg, Wolfgang Hoffmannw,x, Albert Hofmanb, David Karasiky, Douglas P. Kiely, Thomas Kocherr, Maris Kuningasb, Lenore J. Launerg, Kurt K. Lohmanz, Pamela L. Lutseyf, Johan Mackenbacha, Kristin Marcianteaa, Bruce M. Psatyaa,bb, Eric M. Reimancc, Jerome I. Rotterdd, Sudha Seshadrip,q, Michelle D. Shardellee, Albert V. Smithff, Cornelia van Duijnb, Walstongg, M. Carola Zillikenshh, Stefania Bandinelliii,2, Sebastian E. Baumeisterw,2, David A. Bennettn,2, Luigi Ferruccijj,2, Vilmundur Gudnasonff,2, Mika Kivimakii,2, Yongmei Liuz,2, Joanne M. Murabitop,q,2, Anne B. Newmankk,2, Henning Tiemeierb,ll,2,*,

a Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands b Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

f Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, g Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, h Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA i Department of Epidemiology and Public Health, University College London, London, UK j Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

m Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany n Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA o Department of Biostatistics, University of Washington, Seattle, WA, USA

v Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, USA w Institute of Community Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany for Integrated Dementia Care Research (CIDC), a scientific cooperation between the Universities and University Hospitals of Rostock and Greifswald, and the German Center for Neurodegenerative Disease (DZNE), Bonn, Germany y

0197-4580/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2011.05.026

Received 7 January 2011; received in revised form 14 April 2011; accepted 30 May 2011

Abstract

Human longevity and healthy aging show moderate heritability (20%–50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p << 5 “ees” 10(cid:3)8). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p »< | 10(cid:3)5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer’s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

Keywords: Genome-wide association analysis; Mortality; Disease-free survival; Longevity; Aging; Brain aging

1. Introduction

The recent, remarkable extension of life expectancy is largely attributed to the postponement of mortality at old age (Vaupel, 1997, 2010). The years of life gained in the older population residing in developed nations are a success story of public health measures and improved health care. In addition to such external factors, longevity and healthy aging consistently show a modest heritability between 20% and 50% and aging-associated genetic research may provide further insights into the mechanisms of aging (Herskind et al., 1996; McGue et al., 1993; Reed and Dick, 2003). It has been postulated that genes involved in pathways associated with aging identified in animal models, such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipopro- tein metabolism, the mTOR pathway, and the oxidative stress response may also influence survival to old or even exceptionally old age in humans (Christensen et al., 2006; Kenyon, 2010; Vellai et al., 2003). However, in humans, common variants within genes involved in these pathways

to aging in humans may be due to the complexity of the phenotype. One approach to investigate aging and longevity is to compare frequencies of genetic variants between no- nagenarians or centenarians and the general population. This approach led to the discovery of an association be- tween APOE (Deelen et al., 2011; Ewbank, 2007; Gerdes et al., 2000) and more recently FOXO3A (Anselmi et al., 2009; Flachsbart et al., 2009; Li et al., 2009a; Pawlikowska et al., 2009; Willcox et al., 2008) and human aging and longevity. However, a recent genome-wide association study (GWAS) of individuals reaching the age of 90 or older failed to identify genome-wide significant variants (Newman et al.,