Abstract
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 genomewide 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.
| Original language | English (US) |
|---|---|
| Article number | ddu139 |
| Pages (from-to) | 4420-4432 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 23 |
| Issue number | 16 |
| DOIs | |
| State | Published - 2014 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. / Deelen, Joris; Beekman, Marian; Uh, Hae Won; Broer, Linda; Ayers, Kristin L.; Tan, Qihua; Kamatani, Yoichiro; Bennet, Anna M.; Tamm, Riin; Trompet, Stella; Guobjartsson, Daníel F.; Flachsbart, Friederike; Rose, Giuseppina; Viktorin, Alexander; Fischer, Krista; Nygaard, Marianne; Cordell, Heather J.; Crocco, Paolina; Van Den Akker, Erik B.; Böhringer, Stefan; Helmer, Quinta; Nelson, Christopher P.; Saunders, Gary I.; Alver, Maris; Andersen-Ranberg, Karen; Breen, Marie E.; van Der Breggen, Ruud; Caliebe, Amke; Capri, Miriam; Cevenini, Elisa; Collerton, Joanna C.; Dato, Serena; Davies, Karen; Ford, Ian; Gampe, Jutta; Garagnani, Paolo; de Geus, Eco J C; Harrow, Jennifer; Van Heemst, Diana; Heijmans, Bastiaan T.; Heinsen, Femke Anouska; Hottenga, Jouke Jan; Hofman, Albert; Jeune, Bernard; Jonsson, Palmi V.; Lathrop, Mark; Lechner, Doris; Martin-Ruiz, Carmen; Mcnerlan, Susan E.; Mihailov, Evelin; Montesanto, Alberto; Mooijaart, Simon P.; Murphy, Anne; Nohr, Ellen A.; Paternoster, Lavinia; Postmus, Iris; Rivadeneira, Fernando; Ross, Owen A; Salvioli, Stefano; Sattar, Naveed; Schreiber, Stefan; Stefánsson, Hreinn; Stott, David J.; Tiemeier, Henning; Uitterlinden, André G.; Westendorp, Rudi G J; Willemsen, Gonneke; Samani, Nilesh J.; Galan, Pilar; Sørensen, Thorkild I A; Boomsma, Dorret I.; Wouter Jukema, J.; Rea, Irene Maeve; Passarino, Giuseppe; de Craen, Anton J M; Christensen, Kaare; Nebel, Almut; Stefánsson, Kári; Metspalu, Andres; Magnusson, Patrik; Blanché, Hélène; Christiansen, Lene; Kirkwood, Thomas B L; Van Duijn, Cornelia M.; Franceschi, Claudio; Houwing-Duistermaat, Jeanine J.; Slagboom, P. Eline.
In: Human Molecular Genetics, Vol. 23, No. 16, ddu139, 2014, p. 4420-4432.Research output: Contribution to journal › Article
}
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 - Guobjartsson, 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 - Wouter Jukema, J.
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
PY - 2014
Y1 - 2014
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 genomewide 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 genomewide 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.
UR - http://www.scopus.com/inward/record.url?scp=84904741764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904741764&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu139
DO - 10.1093/hmg/ddu139
M3 - Article
C2 - 24688116
AN - SCOPUS:84904741764
VL - 23
SP - 4420
EP - 4432
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 16
M1 - ddu139
ER -