Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 16, Pages 4420-4432Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu139
Keywords
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Funding
- Augustinus Foundation
- Avera Institute for Human Genetics (AIHG)
- AXA Research Fund
- Belfast City Hospital Trust Fund
- Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007]
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Bristol-Myers Squibb
- Center for Inherited Disease Research (CIDR)
- Centre for Medical Systems Biology (CMSB)
- CERA Foundation
- Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG)
- Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR) [11-107308]
- Danish National Research Foundation (DNRF)
- Department of Health and Social Services (Northern Ireland)
- DFG-Cluster of Excellence 'Inflammation at Interfaces'
- Dunhill Medical Trust [R124/0509]
- Egmont Foundation
- Estonian Science Foundation [7859]
- Estonian Government [SF0180142s08]
- European Research Council (ERC) [230374]
- European Science Foundation (ESF) [EU/QLRT-2001-01254]
- European Union [FP5-QLK6-CY-2001-00128, FP6-LIFESCIHEALTH-36894, FP6-LSH M-CT-2004-503270, FP7-HEALTH-2007-B-223004, FP7-HEALTH-F4-2007-201413, FP7-HEALTH-F4-2008-202047, FP7-HEALTH-2009-single-stage-242244, FP7-HEALTH-2010-two-stage-259679]
- Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL
- Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH) [MH081802]
- GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]
- Guy's & St Thomas' NHS Foundation Trust
- Health Foundation
- Heart and Lung foundation [20070481]
- Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]
- Institute for Ageing and Health
- Institut National de la Recherche Agronomique (INRA)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- King's College London
- Medical Research Council (MRC) [G0500997, G0601333]
- Ministere de l'Enseignement superieur et de la Recherche (MESR)
- National Institutes of Health (NIH)/National Institute of Aging (NIA) [P01AG08761, R01D0042157-01A, U01DK066134]
- National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre
- NBIC BioAssist [NWO-NBIC/BioAssist/RK/2008.024]
- Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810]
- Netherlands Genomics Initiative (NGI)
- Netherlands Heart Foundation (NHF) [2001 D 032]
- Netherlands Organization for Scientific Research (NWO, MagW/ZonMW) [904-61-090, 904-61-193, 480-04-004, 400-05-717, Spinozapremie 56-464-14192, 175.010.2005.011, 911-03-012, 985-10-002, Addiction-31160008, Middelg-root-911-09-032]
- Netspar - Living longer for a good health
- NHS North of Tyne (Newcastle Primary Care Trust)
- Pharmacy Foundation
- Regione Autonoma della Sardegna
- Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06]
- Swedish Research Council [M-2005-1112]
- Tampere University Hospital and Academy of Finland
- Danish Interdisciplinary Research Council
- Health Foundation (Helsefonden)
- Ministry for Higher Education
- National Program for Research Infrastructure [09-063256]
- March of Dimes Birth Defects Foundation
- Swedish Foundation for Strategic Research (SSF)
- Unilever Discover Colworth
- Universite Paris 13
- University of Calabria
- University of Tartu [SP1GVAR-ENG]
- Velux Foundation
- VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA)
- Wellcome Trust [084762, 085475, 087436]
- IDEAL [FP7-HEALTH-2010-two-stage-259679]
- Research and Education into Ageing-0153
- European Regional Development Fund
- Biotechnology and Biological Sciences Research Council [BB/I020748/1, BB/F010966/1] Funding Source: researchfish
- Medical Research Council [MR/J50001X/1, G0500997, MR/K006312/1, MR/J012165/1, G0601333] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10170] Funding Source: researchfish
- BBSRC [BB/I020748/1, BB/F010966/1] Funding Source: UKRI
- MRC [G0500997, G0601333, MR/J012165/1, MR/K006312/1, MR/J50001X/1] Funding Source: UKRI
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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.
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