A meta-analysis of genome-wide association studies identifies multiple longevity genes

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity

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

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.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 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 × 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.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 Fundinfo:eu-repo/grantAgreement/EC/FP7/201413info:eu-repo/grantAgreement/EC/FP7/223004info:eu-repo/grantAgreement/EC/FP7/242244info:eu-repo/grantAgreement/EC/FP7/25967