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 genomewide 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 language | English (US) |
---|---|
Article number | ddu139 |
Pages (from-to) | 4420-4432 |
Number of pages | 13 |
Journal | Human molecular genetics |
Volume | 23 |
Issue number | 16 |
DOIs | |
State | Published - Aug 2014 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. / Deelen, Joris; Beekman, Marian; Uh, Hae Won; Broer, Linda; Ayers, Kristin L.; Tan, Qihua; Kamatani, Yoichiro; Bennet, Anna M.; Tamm, Riin; Trompet, Stella; Guobjartsson, 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; Stefánsson, 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.; Wouter Jukema, J.; Rea, Irene Maeve; Passarino, Giuseppe; de Craen, Anton J.M.; Christensen, Kaare; Nebel, Almut; Stefánsson, Kári; 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.
In: Human molecular genetics, Vol. 23, No. 16, ddu139, 08.2014, p. 4420-4432.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age
AU - Deelen, Joris
AU - Beekman, Marian
AU - Uh, Hae Won
AU - Broer, Linda
AU - Ayers, Kristin L.
AU - Tan, Qihua
AU - Kamatani, Yoichiro
AU - Bennet, Anna M.
AU - Tamm, Riin
AU - Trompet, Stella
AU - Guobjartsson, Daníel F.
AU - Flachsbart, Friederike
AU - Rose, Giuseppina
AU - Viktorin, Alexander
AU - Fischer, Krista
AU - Nygaard, Marianne
AU - Cordell, Heather J.
AU - Crocco, Paolina
AU - Van Den Akker, Erik B.
AU - Böhringer, Stefan
AU - Helmer, Quinta
AU - Nelson, Christopher P.
AU - Saunders, Gary I.
AU - Alver, Maris
AU - Andersen-Ranberg, Karen
AU - Breen, Marie E.
AU - van Der Breggen, Ruud
AU - Caliebe, Amke
AU - Capri, Miriam
AU - Cevenini, Elisa
AU - Collerton, Joanna C.
AU - Dato, Serena
AU - Davies, Karen
AU - Ford, Ian
AU - Gampe, Jutta
AU - Garagnani, Paolo
AU - de Geus, Eco J.C.
AU - Harrow, Jennifer
AU - Van Heemst, Diana
AU - Heijmans, Bastiaan T.
AU - Heinsen, Femke Anouska
AU - Hottenga, Jouke Jan
AU - Hofman, Albert
AU - Jeune, Bernard
AU - Jonsson, Palmi V.
AU - Lathrop, Mark
AU - Lechner, Doris
AU - Martin-Ruiz, Carmen
AU - Mcnerlan, Susan E.
AU - Mihailov, Evelin
AU - Montesanto, Alberto
AU - Mooijaart, Simon P.
AU - Murphy, Anne
AU - Nohr, Ellen A.
AU - Paternoster, Lavinia
AU - Postmus, Iris
AU - Rivadeneira, Fernando
AU - Ross, Owen A.
AU - Salvioli, Stefano
AU - Sattar, Naveed
AU - Schreiber, Stefan
AU - Stefánsson, Hreinn
AU - Stott, David J.
AU - Tiemeier, Henning
AU - Uitterlinden, André G.
AU - Westendorp, Rudi G.J.
AU - Willemsen, Gonneke
AU - Samani, Nilesh J.
AU - Galan, Pilar
AU - Sørensen, Thorkild I.A.
AU - Boomsma, Dorret I.
AU - Wouter Jukema, J.
AU - Rea, Irene Maeve
AU - Passarino, Giuseppe
AU - de Craen, Anton J.M.
AU - Christensen, Kaare
AU - Nebel, Almut
AU - Stefánsson, Kári
AU - Metspalu, Andres
AU - Magnusson, Patrik
AU - Blanché, Hélène
AU - Christiansen, Lene
AU - Kirkwood, Thomas B.L.
AU - Van Duijn, Cornelia M.
AU - Franceschi, Claudio
AU - Houwing-Duistermaat, Jeanine J.
AU - Slagboom, P. Eline
N1 - Funding Information: We thank Laurens Wilming from the Wellcome Trust Sanger Institute for the annotation of the lincRNA RP11-524N5.1. This study was undertaken within the framework of European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement no 259679 (IDEAL). A full list of acknowledgments, including support for each study, is provided in Supplementary Material. Funding Information: This work was supported by the Augustinus Foundation; Avera Institute for Human Genetics (AIHG); AXA Research Fund; Belfast City Hospital Trust Fund, Research and Education into Ageing-0153; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI – NL, NWO 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 àL’Energie Atomi-que (CEA)-Centre National de Génotypage (CNG); Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR, grant 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 (grant R124/0509); Egmont Foundation; Estonian Science Foundation (grant 7859); Estonian Government (grant SF0180142s08); European Research Council (ERC, advanced grant 230374); European Science Foundation (ESF, EU/QLRT-2001-01254); European Union’s Fifth/Sixth/ Seventh Framework Programmes (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 and FP7-HEALTH-2010-two-stage-259679); Fondation Caisse d’Epargne Rhône-Alpes Lyon CERAL (2004 – 2007); Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH, grant MH081802); GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254); Guy’s & St Thomas’ NHS Foundation Trust; Health Foundation; Heart and Lung foundation (grant 20070481); Innovation-Oriented Research Program on Genomics (SenterNovem, grant IGE05007); Institute for Ageing and Health; Institut National de la Recherche Agronomique (INRA); Institut National de la Santé et de la Recherche Médicale (INSERM); INTERREG 4A programme Syddanmark-Schleswig-K.E.R.N (with EU funds from the European Regional Development Fund); King’s College London; Medical Research Council (MRC, grant G0500997 and G0601333); Ministère de l’Enseignement supérieur et de la Recherche (MESR); National Institutes of Health (NIH)/National Institute of Aging (NIA, P01AG08761, R01D0042157-01A and 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, grant 050-060-810); Netherlands Genomics Initiative (NGI); Netherlands Heart Foundation (NHF, grant 2001 D 032); Netherlands Organization for Scientific Research (NWO, MagW/ZonMW grant 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 and 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 (grant M-2005-1112); The Competitive Research Funding of the Tampere University Hospital and Academy of Finland; The Danish Interdisciplinary Research Council; The Health Foundation (Helsefonden); The Ministry for Higher Education; The National Program for Research Infrastructure 2007 (grant 09-063256); The March of Dimes Birth Defects Foundation; The Swedish Foundation for Strategic Research (SSF); Unilever Discover Colworth; Université Paris 13; University of Calabria; University of Tartu (grant SP1GVAR-ENG); Velux Foundation; VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); Wellcome Trust (grant 084762, 085475 and 087436). Funding to pay the Open Access publication charges for this article was provided by IDEAL (FP7-HEALTH-2010-two-stage-259679).
PY - 2014/8
Y1 - 2014/8
N2 - 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 genomewide 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.
AB - 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 genomewide 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.
UR - http://www.scopus.com/inward/record.url?scp=84904741764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904741764&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu139
DO - 10.1093/hmg/ddu139
M3 - Article
C2 - 24688116
AN - SCOPUS:84904741764
VL - 23
SP - 4420
EP - 4432
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 16
M1 - ddu139
ER -