Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

J. Deelen, M. Beekman, H.-W. Uh, L. Broer, K.L. Ayers, Q. Tan, Y. Kamatani, A.M. Bennet, R. Tamm, S. Trompet, D.F. Guobjartsson, F. Flachsbart, G. Rose, A. Viktorin, K. Fischer, M. Nygaard, H.J. Cordell, P. Crocco, E.B. Van Den Akker, S. BöhringerQ. Helmer, C.P. Nelson, G.I. Saunders, M. Alver, K. Andersen-Ranberg, M.E. Breen, R. van Der Breggen, A. Caliebe, M. Capri, E. Cevenini, J.C. Collerton, S. Dato, K. Davies, I. Ford, J. Gampe, P. Garagnani, E.J.C. de Geus, J. Harrow, D. Van Heemst, B.T. Heijmans, F.-A. Heinsen, J.-J. Hottenga, A. Hofman, B. Jeune, P.V. Jonsson, M. Lathrop, D. Lechner, C. Martin-Ruiz, S.E. Mcnerlan, E. Mihailov, A. Montesanto, S.P. Mooijaart, A. Murphy, E.A. Nohr, L. Paternoster, I. Postmus, F. Rivadeneira, O.A. Ross, S. Salvioli, N. Sattar, S. Schreiber, H. Stefánsson, D.J. Stott, H. Tiemeier, A.G. Uitterlinden, R.G.J. Westendorp, G. Willemsen, N.J. Samani, P. Galan, T.I.A. Sørensen, D.I. Boomsma, J. Wouter Jukema, I.M. Rea, G. Passarino, A.J.M. de Craen, K. Christensen, A. Nebel, K. Stefánsson, A. Metspalu, P. Magnusson, H. Blanché, L. Christiansen, T.B.L. Kirkwood, C.M. Van Duijn, C. Franceschi, J.J. Houwing-Duistermaat, P.E. Slagboom

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    155 Citations (Scopus)

    Abstract

    The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
    Original languageEnglish
    Pages (from-to)4420-4432
    Number of pages13
    JournalHuman Molecular Genetics
    Volume23
    Issue number16
    Early online date31 Mar 2014
    DOIs
    Publication statusPublished - 15 Aug 2014

    Keywords

    • EMTREE medical terms: aged
    • allele
    • article
    • blood pressure
    • cardiovascular disease
    • cardiovascular risk
    • cerebrovascular accident
    • chromosome 19q
    • chromosome 5q
    • controlled study
    • coronary artery disease
    • disease predisposition
    • Europe
    • female
    • follow up
    • gene linkage disequilibrium
    • gene locus
    • gene mapping
    • gene replication
    • genetic association
    • heritability
    • human
    • hypotension
    • lifespan
    • longevity
    • major clinical study
    • male
    • phenotype
    • pleiotropy
    • priority journal
    • prospective study
    • single nucleotide polymorphism
    • survival
    • very elderly
    • aging
    • Article
    • cardiovascular mortality
    • European
    • genetic risk
    • genetic variability

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