TY - JOUR

T1 - Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

AU - Deelen, Joris

AU - Beekman, Marian

AU - Uh, Hae-Won

AU - Broer, Linda

AU - Ayers, Kristin L

AU - Tan, Qihua

AU - Kamatani, Yoichiro

AU - Bennet, Anna M

AU - Tamm, Riin

AU - Trompet, Stella

AU - Guðbjartsson, Daníel F

AU - Flachsbart, Friederike

AU - Rose, Giuseppina

AU - Viktorin, Alexander

AU - Fischer, Krista

AU - Nygaard, Marianne

AU - Cordell, Heather J

AU - Crocco, Paolina

AU - van den Akker, Erik B

AU - Böhringer, Stefan

AU - Helmer, Quinta

AU - Nelson, Christopher P

AU - Saunders, Gary I

AU - Alver, Maris

AU - Andersen-Ranberg, Karen

AU - Breen, Marie E

AU - van der Breggen, Ruud

AU - Caliebe, Amke

AU - Capri, Miriam

AU - Cevenini, Elisa

AU - Collerton, Joanna C

AU - Dato, Serena

AU - Davies, Karen

AU - Ford, Ian

AU - Gampe, Jutta

AU - Garagnani, Paolo

AU - de Geus, Eco J C

AU - Harrow, Jennifer

AU - van Heemst, Diana

AU - Heijmans, Bastiaan T

AU - Heinsen, Femke-Anouska

AU - Hottenga, Jouke-Jan

AU - Hofman, Albert

AU - Jeune, Bernard

AU - Jonsson, Palmi V

AU - Lathrop, Mark

AU - Lechner, Doris

AU - Martin-Ruiz, Carmen

AU - Mcnerlan, Susan E

AU - Mihailov, Evelin

AU - Montesanto, Alberto

AU - Mooijaart, Simon P

AU - Murphy, Anne

AU - Nohr, Ellen A

AU - Paternoster, Lavinia

AU - Postmus, Iris

AU - Rivadeneira, Fernando

AU - Ross, Owen A

AU - Salvioli, Stefano

AU - Sattar, Naveed

AU - Schreiber, Stefan

AU - Stefánsson, Hreinn

AU - Stott, David J

AU - Tiemeier, Henning

AU - Uitterlinden, André G

AU - Westendorp, Rudi G J

AU - Willemsen, Gonneke

AU - Samani, Nilesh J

AU - Galan, Pilar

AU - Sørensen, Thorkild I A

AU - Boomsma, Dorret I

AU - Jukema, J Wouter

AU - Rea, Irene Maeve

AU - Passarino, Giuseppe

AU - de Craen, Anton J M

AU - Christensen, Kaare

AU - Nebel, Almut

AU - Stefánsson, Kári

AU - Metspalu, Andres

AU - Magnusson, Patrik

AU - Blanché, Hélène

AU - Christiansen, Lene

AU - Kirkwood, Thomas B L

AU - van Duijn, Cornelia M

AU - Franceschi, Claudio

AU - Houwing-Duistermaat, Jeanine J

AU - Slagboom, P Eline

N1 - © The Author 2014. Published by Oxford University Press.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddu139

DO - 10.1093/hmg/ddu139

M3 - Journal article

C2 - 24688116

VL - 23

SP - 4420

EP - 4432

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

ER -