Science, University of Calabria, Rende 87036, Italy, 21Delft Bioinformatics Lab, Delft University of Technology, Delft 2600 GA, The Netherlands, 22Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK, 23NationalInstituteforHealthResearchLeicesterCardiovascularBiomedicalResearchUnit,GlenfieldHospital,Leicester LE3 9QP, UK, 24Human and Vertebrate Analysis and Annotation, The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK, 25School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK, 26Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA, 27Department of Experimental, Diagnostic and Specialty Medicine and 28Interdepartmental Centre ‘L. Galvani’, University of Bologna, Bologna 40126, Italy, 29Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK, 30Robertson Center for Biostatistics and 31Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK, 32Laboratory of Statistical Demography, Max Planck Institute for Demographic Research, Rostock 18057, Germany, 33Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081 BT, The Netherlands, 34EMGO Institute for Health and Care Research, VU UniversityMedicalCenter,Amsterdam1081BT,TheNetherlands,35Geriatrics,LandspitaliUniversityHospital,Reykjavik 101, Iceland, 36Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland, 37Institut de Ge´nomique, CEA, E´ vry 91057, France, 38McGill University and Ge´nome Que´bec Innovation Centre, Montre´al, Que´bec, Canada H3A 1A4, 39Cytogenetics Laboratory, Belfast Health and Social Care Trust, Belfast BT8 8BH, UK, 40Estonian Biocentre, Tartu 51010, Estonia, 41Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus C DK-8000, Denmark, 42MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK, 43Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA, 44BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University of Glasgow, Glasgow G12 8TA, UK, 45PopGen Biobank, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel 24105, Germany, 46Department of Child and Adolescent Psychiatry, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam 3000 CA, The Netherlands, 47Universite´ Sorbonne Paris Cite´-UREN (Unite´ de Recherche en Epide´miologie Nutritionnelle), U557 Inserm; U1125 Inra; Cnam; Universite´ Paris 13, CRNH IdF, Bobigny 93017, France, 48Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark, 49Institute of Preventive Medicine, Bispebjerg and Frederiksberg University Hospitals, Frederiksberg DK-2000, Denmark, 50Interuniversity Cardiology Institute of the Netherlands, Utrecht 3501 DG, The Netherlands, 51IRCCS Institute of Neurological Science, Bellaria Hospital, Bologna 40139, Italy and

CA, The Netherlands, 47Universite´ Sorbonne Paris Cite´-UREN (Unite´ de Recherche en Epide´miologie Nutritionnelle), U557 Inserm; U1125 Inra; Cnam; Universite´ Paris 13, CRNH IdF, Bobigny 93017, France, 48Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark, 49Institute of Preventive Medicine, Bispebjerg and Frederiksberg University Hospitals, Frederiksberg DK-2000, Denmark, 50Interuniversity Cardiology Institute of the Netherlands, Utrecht 3501 DG, The Netherlands, 51IRCCS Institute of Neurological Science, Bellaria Hospital, Bologna 40139, Italy and

Received December 11, 2013; Revised March 6, 2014; Accepted March 25, 2014

∼ 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 5 1.10, P 5 1.74 3 1028). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR 5 0.72, P 5 3.40 3 10236), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n 5 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR 5 0.95, P 5 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 mortalityrisk,independentofbloodpressure.WereportonthefirstGWAS-identifiedlongevitylocusonchromo- some 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.

INTRODUCTION

were further adjusted for the overall genomic inflation factor (l¼ 1.019) (Supplementary Material, Fig. S1). A flow chart of the consecutive analysis steps is depicted in Figure 1.