Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age
2014
Deelen, Joris | Beekman, Marian | Uh, Hae-Won | Broer, Linda | Ayers, Kristin L | Tan, Qihua | Kamatani, Yoichiro | Bennet, Anna M | Tamm, Riin | Trompet, Stella | Guðbjartsson, Daníel F | Flachsbart, Friederike | Rose, Giuseppina | Viktorin, Alexander | Fischer, Krista | Nygaard, Marianne | Cordell, Heather J | Crocco, Paolina | van den Akker, Erik B | Böhringer, Stefan | Helmer, Quinta | Nelson, Christopher P | Saunders, Gary I | Alver, Maris | Andersen-Ranberg, Karen | Breen, Marie E | van Der Breggen, Ruud | Caliebe, Amke | Capri, Miriam | Cevenini, Elisa | Collerton, Joanna C | Dato, Serena | Davies, Karen | Ford, Ian | Gampe, Jutta | Garagnani, Paolo | de Geus, Eco J C | Harrow, Jennifer | van Heemst, Diana | Heijmans, Bastiaan T | Heinsen, Femke-Anouska | Hottenga, Jouke-Jan | Hofman, Albert | Jeune, Bernard | Jonsson, Palmi V | Lathrop, Mark | Lechner, Doris | Martin-Ruiz, Carmen | Mcnerlan, Susan E | Mihailov, Evelin | Montesanto, Alberto | Mooijaart, Simon P | Murphy, Anne | Nohr, Ellen A | Paternoster, Lavinia | Postmus, Iris | Rivadeneira, Fernando | Ross, Owen A | Salvioli, Stefano | Sattar, Naveed | Schreiber, Stefan | Stefansson, Hreinn | Stott, David J | Tiemeier, Henning | Uitterlinden, André G. | Westendorp, Rudi G J | Willemsen, Gonneke | Samani, Nilesh J | Galan, Pilar | Sørensen, Thorkild I A | Boomsma, Dorret I | Jukema, J Wouter | Rea, Irene Maeve | Passarino, Giuseppe | de Craen, Anton J M | Christensen, Kaare | Nebel, Almut | Stefansson, Kari | Metspalu, Andres | Magnusson, Patrik | Blanché, Hélène | Christiansen, Lene | Kirkwood, Thomas B L | van Duijn, Cornelia M | Franceschi, Claudio | Houwing-Duistermaat, Jeanine J | Slagboom, P Eline | Department of Molecular Epidemiology ; German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) | Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA) | Leiden University Medical Center (LUMC) ; Universiteit Leiden = Leiden University | Department of Epidemiology ; The Netherlands Cancer Institute | Institute of Genetic Medicine ; Newcastle University [Newcastle] | National Institute of Public Health ; University of Southern Denmark (SDU) | Department of Clinical Genetics ; Odense University Hospital | Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain | Department of Medical Epidemiology and Biostatistics (MEB) ; Karolinska Institutet [Stockholm] | Tartu University Hospital | Institute of Molecular and Cell Biology ; Faculty of Science and Technology [University of Tartu] ; Tartu Ülikool = University of Tartu [Estonie]-Tartu Ülikool = University of Tartu [Estonie] | Department of Gerontology and Geriatrics ; Leiden University Medical Center (LUMC) ; Universiteit Leiden = Leiden University-Universiteit Leiden = Leiden University | deCODE genetics [Reykjavik] | Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel (CAU) | Università della Calabria [Arcavacata di Rende, Italia] = University of Calabria [Italy] = Université de Calabre [Italie] (UniCal) | Newcastle University [Newcastle] | Delft University of Technology (TU Delft) | Department of Cardiovascular Sciences ; Université Catholique de Louvain = Catholic University of Louvain (UCL) | University Hospitals Leicester | Genome Campus ; The Wellcome Trust Sanger Institute [Cambridge] | School of Medicine, Dentistry and Biomedical Sciences [Belfast] ; Queen's University [Belfast] (QUB) | University of Iowa [Iowa City] | DIMES: Department of Experimental, Diagnostic and Specialty Medicine ; Bologna University Hospital | Institute for Ageing and Health ; Newcastle University [Newcastle] | University of Glasgow | Max Planck Institute for Demographic Research (MPIDR) ; Max-Planck-Gesellschaft | Vrije Universiteit Amsterdam [Amsterdam] (VU) | EMGO Institute for Health and Care Research ; VU University Amsterdam Medical Center | Landspitali National University Hospital of Iceland | University of Iceland [Reykjavik] | McGill University = Université McGill [Montréal, Canada] | Genome Quebec Innovation Centre ; McGill University = Université McGill [Montréal, Canada] | Institut de Génomique | Belfast Health and Social Care Trust | Estonian Biocentre ; Partenaires INRAE | University of Southern Denmark (SDU) | Aarhus University [Aarhus] | School of Social and Community Medicine ; School of Social and Community Medicine | Erasmus University Rotterdam | Mayo Clinic | BHF Glasgow Cardiovascular Research Centre ; University of Glasgow | University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH) ; Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel (CAU) | Institute of Cardiovascular and Medical Sciences ; University of Glasgow | Sophia Children's Hospital | Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)) ; Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM) | 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
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Show more [+] Less [-]English. 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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