title: GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.
abstract: BACKGROUND
  The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
  
  
  METHODS
  We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.
  
  
  RESULTS
  In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).
  
  
  CONCLUSIONS
  We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Broer
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.affiliation: Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Faul
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Massachusetts. NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Massachusetts.
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland. Department of Medicine, University of Iceland, Reykjavik.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biostatistics, University of Washington, Seattle.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Arnold
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland. Department of Medicine, University of Iceland, Reykjavik.
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.affiliation: NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts. Department of Medicine, Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, Massachusetts. Department of Epidemiology, Boston University School of Public Health, Massachusetts.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.
authors.forename: Gudny
authors.initials: G
authors.lastname: Eirkisdottir
authors.affiliation: Rush Institute for Healthy Aging and Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Garcia
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College, Bronx, New York.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kaplan
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor.
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts. Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: School of Medicine, Oregon Health and Science University, Portland.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orwoll
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco.
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.affiliation: Department of Medicine, University of Washington, Seattle. Deparment of Epidemiology, University of Washington, Seattle. Department of Health Services, University of Washington, Seattle. Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Massachusetts. Department of Neurology, Boston University School of Medicine, Massachusetts.
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Child and Adolescent Psychiatry, Erasmus MC and Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland. Department of Medicine, University of Iceland, Reykjavik.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School Department of Medicine, Boston, Massachusetts. Faculty of Medicine in The Galilee, Bar-Ilan University, Safed, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Section of Geriatrics, Boston University School of Medicine and Boston Medical Center, Massachusetts.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Perls
authors.affiliation: Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. Department of Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco. Department of Epidemiology and Biostatistics, University of California, San Francisco.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor.
authors.forename: David R
authors.initials: DR
authors.lastname: Weir
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pennsylvania. *These authors contributed equally to this work.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, The Netherlands. *These authors contributed equally to this work.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: NHLBI's and Boston Univesity's Framingham Heart Study, Massachusetts. Department of Medicine, Section of General Internal Medicine, Boston University School of Medicine, Massachusetts. *These authors contributed equally to this work. murabito@bu.edu.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018092:Kainic Acid Receptors / Q000235:genetics; D000097806:GluK2 Kainate Receptor
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C556123:CADM2 protein, human; C499517:FOXO3 protein, human
keywords: APOE.; FOXO3; GWAS; Longevity