Deelen, Joris3; Beekman, Marian3; Uh, Hae-Won3; Broer, Linda3; Ayers, Kristin L3; Tan, Qihua3; Kamatani, Yoichiro3; Bennet, Anna M3; Tamm, Riin3; Trompet, Stella3; Guðbjartsson, Daníel F3; Flachsbart, Friederike3; Rose, Giuseppina3; Viktorin, Alexander3; Fischer, Krista3; Nygaard, Marianne3; Cordell, Heather J3; Crocco, Paolina3; van den Akker, Erik B3; Böhringer, Stefan3; Helmer, Quinta3; Nelson, Christopher P3; Saunders, Gary I3; Alver, Maris3; Andersen-Ranberg, Karen3; Breen, Marie E3; van der Breggen, Ruud3; Caliebe, Amke3; Capri, Miriam3; Cevenini, Elisa3; Collerton, Joanna C3; Dato, Serena3; Davies, Karen3; Ford, Ian3; Gampe, Jutta3; Garagnani, Paolo3; de Geus, Eco J C3; Harrow, Jennifer3; van Heemst, Diana3; Heijmans, Bastiaan T3; Heinsen, Femke-Anouska3; Hottenga, Jouke-Jan3; Hofman, Albert3; Jeune, Bernard3; Jonsson, Palmi V3; Lathrop, Mark3; Lechner, Doris3; Martin-Ruiz, Carmen3; Mcnerlan, Susan E3; Mihailov, Evelin3; Montesanto, Alberto3; Mooijaart, Simon P3; Murphy, Anne3; Nohr, Ellen A3; Paternoster, Lavinia3; Postmus, Iris3; Rivadeneira, Fernando3; Ross, Owen A3; Salvioli, Stefano3; Sattar, Naveed3; Schreiber, Stefan3; Stefánsson, Hreinn3; Stott, David J3; Tiemeier, Henning3; Uitterlinden, André G3; Westendorp, Rudi G J3; Willemsen, Gonneke3; Samani, Nilesh J3; Galan, Pilar3; Sørensen, Thorkild I A4; Boomsma, Dorret I3; Jukema, J Wouter3; Rea, Irene Maeve3; Passarino, Giuseppe3; de Craen, Anton J M3; Christensen, Kaare3; Nebel, Almut3; Stefánsson, Kári3; Metspalu, Andres3; Magnusson, Patrik3; Blanché, Hélène3; Christiansen, Lene3; Kirkwood, Thomas B L3; van Duijn, Cornelia M3; Franceschi, Claudio3; Houwing-Duistermaat, Jeanine J3; Slagboom, P Eline3
1 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Human Molecular Genetics, 2014, Vol 23, Issue 16, p. 4420-4432