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,21,22 Lenore 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 Andr 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) 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 x 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 x 10^-7 for the combined meta-analysis of CHARGEthat could not be genotyped or imputed in all four CHARGE cohorts, so they were excluded. Of the 22 SNPs selected for genotyping, two could not be genotyped, and four did not pass quality control procedures. Thus, 16 SNPs were analyzed in the second stage. In the Leiden Longevity Study, a total of 950 long-lived proband siblings (mean age 94 years, range 89-104 years), 1,750 offspring (mean age 61 years, range 39-81 years), and 758 partners of offspring (mean age 60 years, range 36-79 years) were included. The additional genotyping of selected SNPs was undertaken in all 950 long-lived probands and compared with the 744 partners of their offspring and an additional 680 blood bank donors (60% men, mean age 31 years, range 18-40 years). All long-lived individuals and comparison groups were from the Leiden area in the Netherlands and of European ancestry.

The study-specific inflation factors (λ) were computed using the set of chi-square statistics used for the meta-analysis for each study to analyze the SNPs. The inflation factor is computed as the median of all chi-square statistics divided by the expected median of the statistics (approximately 0.456) for a chi-square distribution with one degree of freedom. We calculated a meta-analysis odds ratio (OR) for each SNP using a fixed-effects model that combined logistic regression parameters and standard errors across the studies using inverse variance weights. The meta-analysis OR represents the increase in log-odds of surviving to age 90 years or older versus dying between ages 55 and 80 years for each additional copy of the minor allele of the SNP. SNP associations were considered significant on a genome-wide level at p < 5 × 10^-8.