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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-RuizORCiD, 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

Date deposited: 29/09/2014

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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Funding

Funder referenceFunder name
Augustinus Foundation
Avera Institute for Human Genetics (AIHG)
Center for Inherited Disease Research (CIDR)
Centre for Medical Systems Biology (CMSB)
Department of Health and Social Services (Northern Ireland)
DFG-Cluster of Excellence 'Inflammation at Interfaces'
Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL
Guy's & St Thomas' NHS Foundation Trust
Health Foundation
Institut National de la Sante et de la Recherche Medicale (INSERM)
King's College London
Ministry for Higher Education
National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre
Netspar - Living longer for a good health
Pharmacy Foundation
Swedish Foundation for Strategic Research (SSF)
VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA)
AXA Research Fund
Belfast City Hospital Trust Fund
Biotechnology and Biological Sciences Research Council (BBSRC)
Bristol-Myers Squibb
CERA Foundation
Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG)
Danish Interdisciplinary Research Council
Danish National Research Foundation (DNRF)
Egmont Foundation
European Regional Development Fund
Health Foundation (Helsefonden)
Institut National de la Recherche Agronomique (INRA)
Institute for Ageing and Health
March of Dimes Birth Defects Foundation
Ministere de l'Enseignement superieur et de la Recherche (MESR)
Netherlands Genomics Initiative (NGI)
NHS North of Tyne (Newcastle Primary Care Trust)
Regione Autonoma della Sardegna
Research and Education into Ageing-0153
Tampere University Hospital and Academy of Finland
Unilever Discover Colworth
Universite Paris 13
University of Calabria
Velux Foundation
084762Wellcome Trust
085475Wellcome Trust
050-060-810Netherlands Consortium for Healthy Ageing (NCHA)
09-063256National Program for Research Infrastructure
175.010.2005.011Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
087436Wellcome Trust
20070481Heart and Lung foundation
11-107308Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR)
184.021.007Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL)
2001 D 032Netherlands Heart Foundation (NHF)
904-61-193Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
Addiction-31160008Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
230374European Research Council (ERC)
400-05-717Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
480-04-004Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
7859Estonian Science Foundation
904-61-090Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
911-03-012Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
985-10-002Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
FP5-QLK6-CY-2001-00128European Union
FP6-LSH M-CT-2004-503270European Union
FP7-HEALTH-2007-B-223004European Union
FP7-HEALTH-2009-single-stage-242244European Union
FP7-HEALTH-F4-2007-201413European Union
FP7-HEALTH-F4-2008-202047European Union
G0601333Medical Research Council (MRC)
EU/QLRT-2001-01254European Science Foundation (ESF)
EU/QLRT-2001-01254GenomEUtwin
FP6-LIFESCIHEALTH-36894European Union
FP7-HEALTH-2010-two-stage-259679European Union
FP7-HEALTH-2010-two-stage-259679IDEAL
G0500997Medical Research Council (MRC)
IGE05007Innovation-Oriented Research Program on Genomics (SenterNovem)
M-2005-1112Swedish Research Council
NWO-NBIC/BioAssist/RK/2008.024NBIC BioAssist
MH081802Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH)
Middelg-root-911-09-032Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
NIMH U24 MH068457-06Rutgers University Cell and DNA Repository
P01AG08761National Institutes of Health (NIH)/National Institute of Aging (NIA)
QLG2-CT-2002-01254GenomEUtwin
SP1GVAR-ENGUniversity of Tartu
Spinozapremie 56-464-14192Netherlands Organization for Scientific Research (NWO, MagW/ZonMW)
R01D0042157-01ANational Institutes of Health (NIH)/National Institute of Aging (NIA)
R124/0509Dunhill Medical Trust
SF0180142s08Estonian Government
U01DK066134National Institutes of Health (NIH)/National Institute of Aging (NIA)

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