Genome-wide association meta-analysis of human longevity has identified a new locus that confers survival beyond 90 years of age. The study involved Qihua Tan, Yoichiro Kamatani, Anna M. Bennet, Riin Tamm, Stella Trompet, Danel F. Gubjartsson, Friederike Flachsbart, Giuseppina Rose, Alexander Viktorin, Krista Fischer, Marianne Nygaard, Heather J. Cordell, Paolina Crocco, Erik B. van den Akker, Stefan Bohringer, Quinta Helmer, Christopher P. Nelson, Gary I. Saunders, Maris Alver, Karen Andersen-Ranberg, Marie E. Breen, Ruud van der Breggen and others.
The study was conducted by the Department of Molecular Epidemiology and the Netherlands Consortium for Healthy Ageing at Leiden University Medical Center. The Erasmus Medical Center in Rotterdam also participated by contributing to the Department of Epidemiology and the Department of Internal Medicine. Other institutions that contributed include the Institute of Genetic Medicine at Newcastle University; the Institute of Public Health and the Department of Gynecology and Obstetrics at the Institute of Clinical Research at the University of Southern Denmark; the Fondation Jean Dausset-CEPH in Paris; the Karolinska Institute in Stockholm; the Estonian Genome Center and Institute of Molecular and Cell Biology at the University of Tartu in Estonia; and the Population Genomics in Reykjavik.
The study aimed to identify genes associated with longevity beyond 90 years old. The authors found a new locus that confers survival beyond 90 years of age that was not previously reported. The research was published by Oxford University Press in Genetics in 2014.Institut National de la Santé et de la Recherche Médicale (Inserm); U1125 Institut National de la Recherche Agronomique (Inra); Cnam; Université Paris 13, CRNH IdF, Bobigny 93017, France, 48 Novo 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, 49 Institute of Preventive Medicine, Bispebjerg and Frederiksberg University Hospitals, Frederiksberg DK-2000, Denmark, 50 Interuniversity Cardiology Institute of the Netherlands, Utrecht 3501 DG, The Netherlands, 51 IRCCS Institute of Neurological Science, Bellaria Hospital, Bologna 40139, Italy. 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 (aged over 85 years) and 16 121 younger controls (below age 65) 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 over 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=1.743×10^-28). We also confirmed association of rs4420638 on chromosome19q13.32 (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.

INTRODUCTION: Worldwide, human life expectancy has increased remarkably over the last two centuries (1), although healthy life expectancy lags behind. Citizens of the European Union, for example, spend only 75-80% of their lifespan in good health (2). Families in which longevity clusters form an exception in this sense by showing beneficial or youthful profiles for many metabolic and immune-related parameters (3-7) and a low prevalence of common diseases from middle age onwards (5,8,9). Therefore, the genome of long-lived individuals is investigated to identify variants that promote healthy aging and protect against age-related disease. This is a major challenge because the genetic component of lifespan variation in the population at large has been estimated to be only 25% (10,11) and is assumed to be determined by many still uncharacterized genes (12,13). Genetic influences on human longevity are expected to reflect longevity assurance mechanisms acting across species (14), as well as more heterogeneous population-specific effects. Although numerous genome-wide association studies (GWAS) have successfully identified loci involved in common, age-related diseases (15), the corresponding susceptibility loci do not explain the genetic component of human longevity (16). GWAS for human longevity have thus far failed to identify genome-wide significant loci besides the well-known TOMM40/APOE/APOC1 locus (17-19).