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

Lookup NU author(s): Dr Kristin Ayers, Professor Heather Cordell, Dr Joanna Collerton, Dr Karen Davies, Dr Carmen Martin-Ruiz, Emeritus Professor Thomas Kirkwood

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

The genetic contribution to the variation in human lifespan is similar to 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 (a parts per thousand yen85 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 a parts per thousand yen90 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 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 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.


Publication metadata

Author(s): Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guobjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, Van den Akker EB, Bohringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJC, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, Mcnerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefansson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RGJ, Willemsen G, Samani NJ, Galan P, Sorensen TIA, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJM, Christensen K, Nebel A, Stefansson K, Metspalu A, Magnusson P, Blanche H, Christiansen L, Kirkwood TBL, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2014

Volume: 23

Issue: 16

Pages: 4420-4432

Print publication date: 15/08/2014

Online publication date: 31/03/2014

Acceptance date: 25/03/2014

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddu139

DOI: 10.1093/hmg/ddu139


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