title: Birth cohort differences in the prevalence of longevity-associated variants in APOE and FOXO3A in Danish long-lived individuals.
abstract: Gene variants found to associate with human longevity in one population rarely replicate in other populations. The lack of consistent findings may partly be explained by genetic heterogeneity among long-lived individuals due to cohort differences in survival probability. In most high-income countries the probability of reaching e.g. 100years increases by 50-100% per decade, i.e. there is far less selection in more recent cohorts. Here we investigate the cohort specificity of variants in the APOE and FOXO3A genes by comparing the frequencies of the APOE ε4 allele and the minor alleles of two variants in FOXO3A at age 95+ and 100+ in 2712 individuals from the genetically homogeneous Danish birth cohorts 1895-96, 1905, 1910-11, and 1915. Generally, we find a decrease in the allele frequencies of the investigated APOE and FOXO3A variants in individuals from more recent birth cohorts. Assuming a recessive model, this negative trend is significant in 95+ year old individuals homozygous for the APOE ε4 allele (P=0.026) or for the FOXO3A rs7762395 minor allele (P=0.048). For the APOE ε4 allele, the significance is further strengthened when restricting to women (P=0.006). Supportive, but non-significant, trends are found for two of the three tested variants in individuals older than 100years. Altogether, this indicates that cohort differences in selection pressure on survival to the highest ages are reflected in the prevalence of longevity gene variants. Although the effect seems to be moderate, our findings could have an impact on genetic studies of human longevity.
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Electronic address: mnygaard@health.sdu.dk.
authors.forename: Marianne
authors.initials: M
authors.lastname: Nygaard
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Electronic address: rjacobsen@health.sdu.dk.
authors.forename: Rune
authors.initials: R
authors.lastname: Lindahl-Jacobsen
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Electronic address: msoerensen@health.sdu.dk.
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Electronic address: jmengel-from@health.sdu.dk.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mengel-From
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Electronic address: KARanberg@health.sdu.dk.
authors.forename: Karen
authors.initials: K
authors.lastname: Andersen-Ranberg
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Electronic address: BJeune@health.sdu.dk.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jeune
authors.affiliation: The Max-Planck Odense Center on the Biodemography of Aging, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; The Max Planck Institute for Demographic Research, Konrad-Zuse-Straße 1, 18057 Rostock, Germany. Electronic address: jwv@demogr.mpg.de.
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Electronic address: qtan@health.sdu.dk.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Tan
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Electronic address: LChristiansen@health.sdu.dk.
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.affiliation: The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Electronic address: KChristensen@health.sdu.dk.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
mesh_terms: D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics*; D003718:Denmark; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D012641:Selection, Genetic
chemical_list: D001057:Apolipoproteins E; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors
keywords: Apolipoprotein E (APOE); Cohort effects; Forkhead box O3A (FOXO3A); Genetics; Human longevity; Selection