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

Joris Deelen, Marian Beekman, Hae-Won Uh, Linda Broer, Kristin L. Ayers, Qihua Tan, Yoichiro Kamatani, Anna M. Bennet, Riin Tamm, Stella Trompet, Daníel F. Guðbjartsson, Friederike Flachsbart, Giuseppina Rose, Alexander Viktorin, Krista Fischer, Marianne Nygaard, Heather J. Cordell, Paolina Crocco, Erik B. van den Akker, Stefan Böhringer, Quinta Helmer, Christopher P. Nelson, Gary I. Saunders, Maris Alver, Karen Andersen-Ranberg, Marie E. Breen, Ruud van der Breggen, Amke Caliebe, Miriam Capri, Elisa Cevenini, Joanna C. Collerton, Serena Dato, Karen Davies, Ian Ford, Jutta Gampe, Paolo Garagnani, Eco J.C. de Geus, Jennifer Harrow, Diana van Heemst, Bastiaan T. Heijmans, Femke-Anouska Heinsen, Jouke-Jan Hottenga, Albert Hofman, Bernard Jeune, Palmi V. Jonsson, Mark Lathrop, Doris Lechner, Carmen Martin-Ruiz, Susan E. Mcnerlan, Evelin Mihailov, Alberto Montesanto, Simon P. Mooijaart, Anne Murphy, Ellen A. Nohr, Lavinia Paternoster, Iris Postmus, Fernando Rivadeneira, Owen A. Ross, Stefano Salvioli, Naveed Sattar, Stefan Schreiber, Hreinn Stefánsson, David J. Stott, Henning Tiemeier, André G. Uitterlinden, Rudi G.J. Westendorp, Gonneke Willemsen, Nilesh J. Samani, Pilar Galan, Thorkild I.A. Sørensen, Dorret I. Boomsma, J. Wouter Jukema, Irene Maeve Rea, Giuseppe Passarino, Anton J.M. de Craen, Kaare Christensen, Almut Nebel, Kári Stefánsson, Andres Metspalu, Patrik Magnusson, Hélène Blanché, Lene Christiansen, Thomas B.L. Kirkwood, Cornelia M. van Duijn, Claudio Franceschi, Jeanine J. Houwing-Duistermaat, P. Eline Slagboom

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.