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 Guðbjartsson; Friederike Flachsbart; Giuseppina Rose; Alexander Viktorin; Krista Fischer; Marianne Nygaard; Heather J Cordell; Paolina Crocco; Erik B van den Akker; Stefan Böhringer; Quinta 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

doi:10.1093/hmg/ddu139

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 Guðbjartsson, 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

Institut for Folkesundhedsvidenskab

151 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Human Molecular Genetics
Vol/bind	23
Udgave nummer	16
Sider (fra-til)	4420-4432
Antal sider	13
ISSN	0964-6906
DOI	https://doi.org/10.1093/hmg/ddu139
Status	Udgivet - 15 aug. 2014

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10.1093/hmg/ddu139

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Deelen, J., Beekman, M., Uh, H-W., Broer, L., Ayers, K. L., Tan, Q., Kamatani, Y., Bennet, A. M., Tamm, R., Trompet, S., Guðbjartsson, D. F., Flachsbart, F., Rose, G., Viktorin, A., Fischer, K., Nygaard, M., Cordell, H. J., Crocco, P., van den Akker, E. B., ... 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. https://doi.org/10.1093/hmg/ddu139

Deelen, J, Beekman, M, Uh, H-W, Broer, L, Ayers, KL, Tan, Q, Kamatani, Y, Bennet, AM, Tamm, R, Trompet, S, Guðbjartsson, 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, F-A, Hottenga, J-J, 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, Jukema, JW, 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, bind 23, nr. 16, s. 4420-4432. https://doi.org/10.1093/hmg/ddu139

@article{87b6edf98fb246e99d0c698ffc09e2a4,

title = "Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age",

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.",

author = "Joris Deelen and Marian Beekman and Hae-Won Uh and Linda Broer and Ayers, {Kristin L} and Qihua Tan and Yoichiro Kamatani and Bennet, {Anna M} and Riin Tamm and Stella Trompet and Gu{\dh}bjartsson, {Dan{\'i}el F} and Friederike Flachsbart and Giuseppina Rose and Alexander Viktorin and Krista Fischer and Marianne Nygaard and Cordell, {Heather J} and Paolina Crocco and {van den Akker}, {Erik B} and Stefan B{\"o}hringer and Quinta Helmer and Nelson, {Christopher P} and Saunders, {Gary I} and Maris Alver and Karen Andersen-Ranberg and Breen, {Marie E} and {van der Breggen}, Ruud and Amke Caliebe and Miriam Capri and Elisa Cevenini and Collerton, {Joanna C} and Serena Dato and Karen Davies and Ian Ford and Jutta Gampe and Paolo Garagnani and {de Geus}, {Eco J C} and Jennifer Harrow and {van Heemst}, Diana and Heijmans, {Bastiaan T} and Femke-Anouska Heinsen and Jouke-Jan Hottenga and Albert Hofman and Bernard Jeune and Jonsson, {Palmi V} and Mark Lathrop and Doris Lechner and Carmen Martin-Ruiz and Mcnerlan, {Susan E} and Evelin Mihailov and Alberto Montesanto and Mooijaart, {Simon P} and Anne Murphy and Nohr, {Ellen A} and Lavinia Paternoster and Iris Postmus and Fernando Rivadeneira and Ross, {Owen A} and Stefano Salvioli and Naveed Sattar and Stefan Schreiber and Hreinn Stef{\'a}nsson and Stott, {David J} and Henning Tiemeier and Uitterlinden, {Andr{\'e} G} and Westendorp, {Rudi G J} and Gonneke Willemsen and Samani, {Nilesh J} and Pilar Galan and S{\o}rensen, {Thorkild I A} and Boomsma, {Dorret I} and Jukema, {J Wouter} and Rea, {Irene Maeve} and Giuseppe Passarino and {de Craen}, {Anton J M} and Kaare Christensen and Almut Nebel and K{\'a}ri Stef{\'a}nsson and Andres Metspalu and Patrik Magnusson and H{\'e}l{\`e}ne Blanch{\'e} and Lene Christiansen and Kirkwood, {Thomas B L} and {van Duijn}, {Cornelia M} and Claudio Franceschi and Houwing-Duistermaat, {Jeanine J} and Slagboom, {P Eline}",

note = "{\textcopyright} The Author 2014. Published by Oxford University Press.",

year = "2014",

month = aug,

day = "15",

doi = "10.1093/hmg/ddu139",

language = "English",

volume = "23",

pages = "4420--4432",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

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

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 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.

U2 - 10.1093/hmg/ddu139

DO - 10.1093/hmg/ddu139

M3 - Journal article

C2 - 24688116

SN - 0964-6906

VL - 23

SP - 4420

EP - 4432

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

ER -

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

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