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, Stefan Walter, Kathryn L. Lunetta, Melissa E. Garcia, P. Eline Slagboom, Kaare Christensen, Alice M. Arnold, Thor Aspelund, Yurii S. Aulchenko, Emelia J. Benjamin, Lene Christiansen, Ralph B. D'Agostino, Annette L. Fitzpatrick, Nora Franceschini, Nicole L. Glazer, Vilmundur Gudnason, Albert Hofman, Robert Kaplan, David Karasik, Margaret Kelly-HayesDouglas P. Kiel, Lenore J. Launer, Kristin D. Marciante, Joseph M. Massaro, Iva Miljkovic, Michael A. Nalls, Dena Hernandez, Bruce M. Psaty, Fernando Rivadeneira, Jerome Rotter, Sudha Seshadri, Albert V. Smith, Kent D. Taylor, Henning Tiemeier, Hae Won Uh, André G. Uitterlinden, James W. Vaupel, Jeremy Walston, Rudi G.J. Westendorp, Tamara B. Harris, Thomas Lumley, Cornelia M. Van Duijn, Joanne M. Murabito

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

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) Consortium. 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 (chromosome 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 findings.

Original languageEnglish
Pages (from-to)478-487
Number of pages10
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume65 A
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Bibliographical note

Funding Information:
The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant numbers U01 HL080295 and R01 HL087652 from the NHLBI and R01 AG023629 from the NIA, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The FHS phenotype–genotype analyses were supported by the NIA grant numbers R01AG029451, R01AG028321, R01AG033193, and R01 AG031287. The FHS of the NHLBI of the National Institutes of Health (NIH) and Boston University School of Medicine were supported by the NHLBI’s FHS contract number N01-HC-25195 and its contract with Affymetrix, Inc. for genotyping services (contract number N02-HL-6-4278). Analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP HealthAssociation Resource project.A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. D.P.K.’s effort was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the NIA (R01 AR/AG 41398). The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; and the European Commission (DG XII). The genetic analyses were supported by the Netherlands Organization for Scientific Research grant number 175.01.2005.011. This study was supported by the Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (nr 050-060-810). The work of S.W. was supported by Netspar. The AGES-Reykjavik is funded by NIH contract number N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA Intramural Research Program Laboratory of Neurogenetics. The Leiden Longevity Study was supported by the Innovation Oriented research Program on Genomics, the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Aging in the framework of the Netherlands Genomics Initiative, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development (ZonMw), the Danish National Programme for Research Infrastructure 2007 from the Danish Agency for Science Technology and Innovation, and Unilever PLC, UK. The Longevity Consortium, funded by the NIA, grant number U19 AG023122, provided administrative resources to CHARGE investigators for this phenotype as well as scientific opportunity funds to conduct follow-up genotyping. The Danish 1905 Cohort Survey was supported by grants from the Danish National Research Foundation and NIH/NIA grant P01 AG08761. The Danish Aging Research Center is supported by a grant from the Velux Foundation. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contract numbers N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract number U01HG004402; and NIH contract number HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research.

Funding

The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant numbers U01 HL080295 and R01 HL087652 from the NHLBI and R01 AG023629 from the NIA, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The FHS phenotype–genotype analyses were supported by the NIA grant numbers R01AG029451, R01AG028321, R01AG033193, and R01 AG031287. The FHS of the NHLBI of the National Institutes of Health (NIH) and Boston University School of Medicine were supported by the NHLBI’s FHS contract number N01-HC-25195 and its contract with Affymetrix, Inc. for genotyping services (contract number N02-HL-6-4278). Analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP HealthAssociation Resource project.A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. D.P.K.’s effort was supported by a grant from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the NIA (R01 AR/AG 41398). The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; and the European Commission (DG XII). The genetic analyses were supported by the Netherlands Organization for Scientific Research grant number 175.01.2005.011. This study was supported by the Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (nr 050-060-810). The work of S.W. was supported by Netspar. The AGES-Reykjavik is funded by NIH contract number N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA Intramural Research Program Laboratory of Neurogenetics. The Leiden Longevity Study was supported by the Innovation Oriented research Program on Genomics, the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Aging in the framework of the Netherlands Genomics Initiative, the Netherlands Organization for Scientific Research, the Netherlands Organization for Health Research and Development (ZonMw), the Danish National Programme for Research Infrastructure 2007 from the Danish Agency for Science Technology and Innovation, and Unilever PLC, UK. The Longevity Consortium, funded by the NIA, grant number U19 AG023122, provided administrative resources to CHARGE investigators for this phenotype as well as scientific opportunity funds to conduct follow-up genotyping. The Danish 1905 Cohort Survey was supported by grants from the Danish National Research Foundation and NIH/NIA grant P01 AG08761. The Danish Aging Research Center is supported by a grant from the Velux Foundation. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contract numbers N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract number U01HG004402; and NIH contract number HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research.

FundersFunder number
Netherlands Consortium for Healthy Aging
Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy AgingN01-AG-12100, 050-060-810
Research Institute for Diseases in the Elderly
Robert Dawson Evans Endowment
Southern California Diabetes Endocrinology Research CenterR01AG033193, R01AG029451, R01 AG031287, R01AG028321
Unilever PLCU19 AG023122
National Institutes of HealthN02-HL-6-4278, N01-HC-25195
National Institute on Aging
National Heart, Lung, and Blood InstituteR01 AG023629
National Human Genome Research InstituteU01HG004402, HHSN268200625226C, UL1RR025005
National Institute of Diabetes and Digestive and Kidney DiseasesK01DK083029, DK063491
National Institute of Neurological Disorders and Stroke
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01 AR/AG 41398
National Center for Research ResourcesM01-RR00425
Velux FondenN01-HC-55021, N01-HC-55020, R01HL59367, N01-HC-55022, N01-HC-55018, N01-HC-55016, N01-HC-55015, R01HL087641, N01-HC-55019, R01HL086694
European Commission
Danmarks GrundforskningsfondP01 AG08761
Danish Agency for Science and Higher Education
ZonMw
Erasmus Universiteit Rotterdam
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum
Ministerie van Onderwijs, Cultuur en Wetenschap
Nederlandse Organisatie voor Wetenschappelijk Onderzoek175.01.2005.011
Hjartavernd
Centre for Medical Systems Biology

    Keywords

    • Genome-wide association study
    • Longevity
    • Meta-analysis

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