Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age
Joris Deelen
(1, 2)
,
Marian Beekman
(1, 2)
,
Hae-Won Uh
(3)
,
Linda Broer
(2, 4)
,
Kristin L Ayers
(5)
,
Qihua Tan
(6, 7)
,
Yoichiro Kamatani
(8)
,
Anna M Bennet
(9)
,
Riin Tamm
(10, 11)
,
Stella Trompet
(3, 12)
,
Daníel F Guðbjartsson
(13)
,
Friederike Flachsbart
(14)
,
Giuseppina Rose
(15)
,
Alexander Viktorin
(9)
,
Krista Fischer
(10)
,
Marianne Nygaard
(6)
,
Heather J Cordell
(16)
,
Paolina Crocco
(15)
,
Erik B van den Akker
(1, 17)
,
Stefan Böhringer
(3)
,
Quinta Helmer
(3)
,
Christopher P Nelson
(18, 19)
,
Gary I Saunders
(20)
,
Maris Alver
(10, 11)
,
Karen Andersen-Ranberg
(6)
,
Marie E Breen
(21, 22)
,
Ruud van Der Breggen
(1)
,
Amke Caliebe
(14)
,
Miriam Capri
(23)
,
Elisa Cevenini
(23)
,
Joanna C Collerton
(24)
,
Serena Dato
(15)
,
Karen Davies
(24)
,
Ian Ford
(25)
,
Jutta Gampe
(26)
,
Paolo Garagnani
(23)
,
Eco J C de Geus
(27, 28)
,
Jennifer Harrow
(20)
,
Diana van Heemst
(12)
,
Bastiaan T Heijmans
(1, 2)
,
Femke-Anouska Heinsen
(14)
,
Jouke-Jan Hottenga
(27)
,
Albert Hofman
(2, 4)
,
Bernard Jeune
(6)
,
Palmi V Jonsson
(29, 30)
,
Mark Lathrop
(8, 28, 31, 32)
,
Doris Lechner
(33)
,
Carmen Martin-Ruiz
(24)
,
Susan E Mcnerlan
(21, 34)
,
Evelin Mihailov
(10, 35)
,
Alberto Montesanto
(15)
,
Simon P Mooijaart
(2, 12)
,
Anne Murphy
(21)
,
Ellen A Nohr
(36, 37)
,
Lavinia Paternoster
(38)
,
Iris Postmus
(2, 12)
,
Fernando Rivadeneira
(2, 4, 39)
,
Owen A Ross
(21, 40)
,
Stefano Salvioli
(23)
,
Naveed Sattar
(41)
,
Stefan Schreiber
(14, 42)
,
Hreinn Stefansson
(13)
,
David J Stott
(43)
,
Henning Tiemeier
(2, 4, 44)
,
André G. Uitterlinden
(2, 4, 39)
,
Rudi G J Westendorp
(2, 12)
,
Gonneke Willemsen
(27)
,
Nilesh J Samani
(18, 19)
,
Pilar Galan
(45)
,
Thorkild I A Sørensen
,
Dorret I Boomsma
(27)
,
J Wouter Jukema
(3)
,
Irene Maeve Rea
(21)
,
Giuseppe Passarino
(15)
,
Anton J M de Craen
(12)
,
Kaare Christensen
(6, 7)
,
Almut Nebel
(14)
,
Kari Stefansson
(13)
,
Andres Metspalu
(10, 11, 35)
,
Patrik Magnusson
(9)
,
Hélène Blanché
(8)
,
Lene Christiansen
(6, 7)
,
Thomas B L Kirkwood
(24)
,
Cornelia M van Duijn
(2, 4)
,
Claudio Franceschi
(23)
,
Jeanine J Houwing-Duistermaat
(3)
,
P Eline Slagboom
(1, 2)
1
Department of Molecular Epidemiology
2 NCHA - Netherlands Consortium for Healthy Aging [Leiden, Netherlands]
3 LUMC - Leiden University Medical Center
4 Department of Epidemiology
5 Institute of Genetic Medicine
6 National Institute of Public Health
7 Department of Clinical Genetics
8 Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain
9 MEB - Department of Medical Epidemiology and Biostatistics
10 University of Tartu
11 Institute of Molecular and Cell Biology
12 Department of Gerontology and Geriatrics
13 deCODE genetics [Reykjavik]
14 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
15 UniCal - Università della Calabria [Arcavacata di Rende, Italia] = University of Calabria [Italy] = Université de Calabre [Italie]
16 Newcastle University [Newcastle]
17 TU Delft - Delft University of Technology
18 Department of Cardiovascular Sciences
19 University Hospitals Leicester
20 Genome Campus
21 School of Medicine, Dentistry and Biomedical Sciences [Belfast]
22 University of Iowa [Iowa City]
23 DIMES: Department of Experimental, Diagnostic and Specialty Medicine
24 Institute for Ageing and Health
25 University of Glasgow
26 MPIDR - Max Planck Institute for Demographic Research
27 VU - Vrije Universiteit Amsterdam [Amsterdam]
28 EMGO Institute for Health and Care Research
29 Landspitali National University Hospital of Iceland
30 University of Iceland [Reykjavik]
31 McGill University = Université McGill [Montréal, Canada]
32 Genome Quebec Innovation Centre
33 Institut de Génomique
34 Belfast Health and Social Care Trust
35 Estonian Biocentre
36 SDU - University of Southern Denmark
37 Aarhus University [Aarhus]
38 School of Social and Community Medicine
39 Erasmus University Rotterdam
40 Mayo Clinic
41 BHF Glasgow Cardiovascular Research Centre
42 University Medical Center Schleswig-Holstein
43 Institute of Cardiovascular and Medical Sciences
44 Sophia Children's Hospital
45 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
2 NCHA - Netherlands Consortium for Healthy Aging [Leiden, Netherlands]
3 LUMC - Leiden University Medical Center
4 Department of Epidemiology
5 Institute of Genetic Medicine
6 National Institute of Public Health
7 Department of Clinical Genetics
8 Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain
9 MEB - Department of Medical Epidemiology and Biostatistics
10 University of Tartu
11 Institute of Molecular and Cell Biology
12 Department of Gerontology and Geriatrics
13 deCODE genetics [Reykjavik]
14 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
15 UniCal - Università della Calabria [Arcavacata di Rende, Italia] = University of Calabria [Italy] = Université de Calabre [Italie]
16 Newcastle University [Newcastle]
17 TU Delft - Delft University of Technology
18 Department of Cardiovascular Sciences
19 University Hospitals Leicester
20 Genome Campus
21 School of Medicine, Dentistry and Biomedical Sciences [Belfast]
22 University of Iowa [Iowa City]
23 DIMES: Department of Experimental, Diagnostic and Specialty Medicine
24 Institute for Ageing and Health
25 University of Glasgow
26 MPIDR - Max Planck Institute for Demographic Research
27 VU - Vrije Universiteit Amsterdam [Amsterdam]
28 EMGO Institute for Health and Care Research
29 Landspitali National University Hospital of Iceland
30 University of Iceland [Reykjavik]
31 McGill University = Université McGill [Montréal, Canada]
32 Genome Quebec Innovation Centre
33 Institut de Génomique
34 Belfast Health and Social Care Trust
35 Estonian Biocentre
36 SDU - University of Southern Denmark
37 Aarhus University [Aarhus]
38 School of Social and Community Medicine
39 Erasmus University Rotterdam
40 Mayo Clinic
41 BHF Glasgow Cardiovascular Research Centre
42 University Medical Center Schleswig-Holstein
43 Institute of Cardiovascular and Medical Sciences
44 Sophia Children's Hospital
45 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
Naveed Sattar
- Fonction : Auteur
- PersonId : 762622
- ORCID : 0000-0002-1604-2593
Henning Tiemeier
- Fonction : Auteur
- PersonId : 763597
- ORCID : 0000-0002-4395-1397
Thorkild I A Sørensen
- Fonction : Auteur
Hélène Blanché
- Fonction : Auteur
- PersonId : 766613
- ORCID : 0000-0003-2115-575X
Claudio Franceschi
- Fonction : Auteur
- PersonId : 762867
- ORCID : 0000-0001-9841-6386
- IdRef : 172478790
P Eline Slagboom
- Fonction : Auteur correspondant
Résumé
The genetic contribution to the variation in human lifespan is similar to 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 (a parts per thousand yen85 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 a parts per thousand yen90 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 x 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 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.