A Meta-analysis of Four Genome-Wide Association Studies of Survival to Age 90 Years or Older: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Anne B. Newman,1,* Stefan Walter,2,3,*,† Kathryn L. Lunetta,4,5,* Melissa E. Garcia,6,* P. Eline Slagboom,7 Kaare Christensen,8 Alice M. Arnold,9 Thor Aspelund,10 Yurii S. Aulchenko,2,† Emelia J. Benjamin,4,11,12,13 Lene Christiansen,8 Ralph B. D’Agostino Sr,4,14 Annette L. Fitzpatrick,15 Nora Franceschini,16 Nicole L. Glazer,17,18 Vilmundur Gudnason,10,19 Albert Hofman,2,† Robert Kaplan,20 David Karasik,21,22 Margaret Kelly-Hayes,4,23 Douglas P. Kiel,21,22Lenore J. Launer,6 Kristin D. Marciante,17,18

M. Psaty,15,17,18,25 Fernando Rivadeneira,2,26,† Jerome Rotter,27 Sudha Seshadri,23 Albert V. Smith,18 Kent D. Taylor,27 Henning Tiemeier,2,28,† Hae-Won Uh,29 André G. Uitterlinden,2,26,† James W. Vaupel,30 Jeremy Walston,31 Rudi G. J. Westendorp,32 Tamara B. Harris,6,* Thomas Lumley,9,* Cornelia M. van Duijn,2,*,† and Joanne M. Murabito4,33,*

1Cardiovascular Health Study, Department of Epidemiology, University of Pittsburgh, Pennsylvania. 2Rotterdam Study, Department of Epidemiology and Biostatistics and 3Department of Public Health, Erasmus Medical

4Framingham Heart Study, The National Heart Lung and Blood Institute, Massachusetts. 5Framingham Heart Study, Department of Biostatistics, Boston University School of Public Health, Massachusetts. 6Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), Laboratory of Epidemiology, Biometry and Demography, Intramural Research Program, National Institute on Aging, Bethesda, Maryland. 7Leiden Longevity Study, Netherlands Consortium for Healthy Ageing: Section of Molecular Epidemiology, Leiden University Medical

9Cardiovascular Health Study, Department of Biostatistics, University of Washington, Seattle. Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), University of Iceland School of Medicine, Reykjavik, Iceland. 11Framingham Heart Study, Department of Cardiology and 12Department of Preventive Medicine, Boston University School of Medicine, Massachusetts.

19Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), Icelandic Heart Association, Iceland. Health Study, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York. 21Framingham Heart Study, Hebrew Senior Life Institute for Aging Research, Boston, Massachusetts.

23Framingham Heart Study, Department of Neurology, Boston University School of Medicine, Massachusetts. 24Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland.

Address correspondence to Anne B. Newman, MD, MPH, Department of Epidemiology, Graduate School of Public Health, 130 North Bellefield Avenue, Suite 500, University of Pittsburgh, Pittsburgh, PA 15213. Email: newmana@edc.pitt.edu

Background. Genome-wide association studies (GWAS) may yield insights into longevity.

Methods. We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/ Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Con- sortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

Results. There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 × 10−8. Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 × 10−7 for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chro- mosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

Conclusion. Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial

Key Words: Longevity—Genome-wide association study—Meta-analysis.

Received September 22, 2009; Accepted February 15, 2010

Decision Editor: Luigi Ferrucci, MD, PhD

Two previous studies have used whole-genome screening to identify genetic variants associated with longevity (20,21). In a linkage analysis, the earliest report (20) identi- fied a locus on chromosome 4 that has not been replicated. A recent report from the Framingham Heart Study (FHS) (22) identified modest associations between longevity (or age at death) and single-nucleotide polymorphisms (SNPs) in or near important candidate genes, including FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN, but none of the associations achieved conventional levels of sta- tistical significance; the sample size was modest, and the genotyping platform did not cover the genome well by cur- rent standards. The advent of genome-wide association studies (GWAS) has successfully led to the discovery of novel genetic variants that have strong evidence for replica- tion and that are outside of traditional candidate gene re- gions for several common diseases (23–29). The detection of novel genetic variants associated with longevity holds the promise to provide important insights to biologic pathways in the aging process and thus the potential to develop inno- vative strategies to promote a long and healthy life.