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. Guobjartsson, Friederike Flachsbart, Giuseppina Rose, Alexander Viktorin, Krista Fischer, Marianne Nygaard, Heather J. Cordell, Paolina Crocco, Erik B. Van Den Akker, Stefan BöhringerQuinta 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

Research output: Contribution to journalArticle

122 Citations (Scopus)

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 languageEnglish (US)
Article numberddu139
Pages (from-to)4420-4432
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number16
DOIs
StatePublished - 2014

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Alleles
Chromosomes
Survival
Hypotension
Blood Pressure
Mortality
Disease Susceptibility
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Deelen, J., Beekman, M., Uh, H. W., Broer, L., Ayers, K. L., Tan, Q., ... Slagboom, P. E. (2014). Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Human Molecular Genetics, 23(16), 4420-4432. [ddu139]. https://doi.org/10.1093/hmg/ddu139

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 journalArticle

Deelen, J, Beekman, M, Uh, HW, Broer, L, Ayers, KL, Tan, Q, Kamatani, Y, Bennet, AM, Tamm, R, Trompet, S, Guobjartsson, DF, Flachsbart, F, Rose, G, Viktorin, A, Fischer, K, Nygaard, M, Cordell, HJ, Crocco, P, Van Den Akker, EB, Böhringer, S, Helmer, Q, Nelson, CP, Saunders, GI, Alver, M, Andersen-Ranberg, K, Breen, ME, van Der Breggen, R, Caliebe, A, Capri, M, Cevenini, E, Collerton, JC, Dato, S, Davies, K, Ford, I, Gampe, J, Garagnani, P, de Geus, EJC, Harrow, J, Van Heemst, D, Heijmans, BT, Heinsen, FA, Hottenga, JJ, Hofman, A, Jeune, B, Jonsson, PV, Lathrop, M, Lechner, D, Martin-Ruiz, C, Mcnerlan, SE, Mihailov, E, Montesanto, A, Mooijaart, SP, Murphy, A, Nohr, EA, Paternoster, L, Postmus, I, Rivadeneira, F, Ross, OA, Salvioli, S, Sattar, N, Schreiber, S, Stefánsson, H, Stott, DJ, Tiemeier, H, Uitterlinden, AG, Westendorp, RGJ, Willemsen, G, Samani, NJ, Galan, P, Sørensen, TIA, Boomsma, DI, Wouter Jukema, J, Rea, IM, Passarino, G, de Craen, AJM, Christensen, K, Nebel, A, Stefánsson, K, Metspalu, A, Magnusson, P, Blanché, H, Christiansen, L, Kirkwood, TBL, Van Duijn, CM, Franceschi, C, Houwing-Duistermaat, JJ & Slagboom, PE 2014, 'Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age', Human Molecular Genetics, vol. 23, no. 16, ddu139, pp. 4420-4432. https://doi.org/10.1093/hmg/ddu139
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. / Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 16. pp. 4420-4432.
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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.",
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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.

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

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