Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Marian Beekman; Hélène Blanché; Markus Perola; Anti Hervonen; Vladyslav Bezrukov; Ewa Sikora; Lene Christiansen; Friederike Flachsbart; Anton J M De Craen; Tom B L Kirkwood; Irene Maeve Rea; Michel Poulain; Jean-Marie Robine; Silvana Valensin; Maria Antonietta Stazi; Giuseppe Passarino; Luca Deiana; Efstathios S Gonos; Lavinia Paternoster; Thorkild I A Sørensen; Qihua Tan; Quinta Helmer; Erik B van den Akker; Joris Deelen; Francesca Martella; Heather J Cordell; Kristin L Ayers; James W. Vaupel; Outi Törnwall; Thomas E Johnson; Stefan Schreiber; Mark Lathrop; Axel Skytthe; Rudi G J Westendorp; Kaare Christensen; Jutta Gampe; Almut Nebel; Jeanine J Houwing-Duistermaat; Pieternella Eline Slagboom; Claudio Franceschi; GEHA consortium

doi:10.1111/acel.12039

Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Marian Beekman, Hélène Blanché, Markus Perola, Anti Hervonen, Vladyslav Bezrukov, Ewa Sikora, Lene Christiansen, Friederike Flachsbart, Anton J M De Craen, Tom B L Kirkwood, Irene Maeve Rea, Michel Poulain, Jean-Marie Robine, Silvana Valensin, Maria Antonietta Stazi, Giuseppe Passarino, Luca Deiana, Efstathios S Gonos, Lavinia Paternoster, Thorkild I A SørensenQihua Tan, Quinta Helmer, Erik B van den Akker, Joris Deelen, Francesca Martella, Heather J Cordell, Kristin L Ayers, James W. Vaupel, Outi Törnwall, Thomas E Johnson, Stefan Schreiber, Mark Lathrop, Axel Skytthe, Rudi G J Westendorp, Kaare Christensen, Jutta Gampe, Almut Nebel, Jeanine J Houwing-Duistermaat, Pieternella Eline Slagboom, Claudio Franceschi, GEHA consortium

Department of Public Health

124 Citations (Scopus)

Abstract

Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10^-8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10^-5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Original language	English
Journal	Aging Cell
Volume	12
Issue number	2
Pages (from-to)	184-193
Number of pages	10
ISSN	1474-9718
DOIs	https://doi.org/10.1111/acel.12039
Publication status	Published - 2013

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10.1111/acel.12039

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Beekman, M., Blanché, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., Christiansen, L., Flachsbart, F., De Craen, A. J. M., Kirkwood, T. B. L., Rea, I. M., Poulain, M., Robine, J-M., Valensin, S., Stazi, M. A., Passarino, G., Deiana, L., Gonos, E. S., Paternoster, L., ... consortium, GEHA. (2013). Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. Aging Cell, 12(2), 184-193. https://doi.org/10.1111/acel.12039

Beekman, M, Blanché, H, Perola, M, Hervonen, A, Bezrukov, V, Sikora, E, Christiansen, L, Flachsbart, F, De Craen, AJM, Kirkwood, TBL, Rea, IM, Poulain, M, Robine, J-M, Valensin, S, Stazi, MA, Passarino, G, Deiana, L, Gonos, ES, Paternoster, L, Sørensen, TIA, Tan, Q, Helmer, Q, van den Akker, EB, Deelen, J, Martella, F, Cordell, HJ, Ayers, KL, Vaupel, JW, Törnwall, O, Johnson, TE, Schreiber, S, Lathrop, M, Skytthe, A, Westendorp, RGJ, Christensen, K, Gampe, J, Nebel, A, Houwing-Duistermaat, JJ, Slagboom, PE, Franceschi, C & consortium, GEHA 2013, 'Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study', Aging Cell, vol. 12, no. 2, pp. 184-193. https://doi.org/10.1111/acel.12039

@article{67fa057c4375494a9e88b639b43057c5,

title = "Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study",

abstract = "Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10-8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10-5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.",

author = "Marian Beekman and H{\'e}l{\`e}ne Blanch{\'e} and Markus Perola and Anti Hervonen and Vladyslav Bezrukov and Ewa Sikora and Lene Christiansen and Friederike Flachsbart and {De Craen}, {Anton J M} and Kirkwood, {Tom B L} and Rea, {Irene Maeve} and Michel Poulain and Jean-Marie Robine and Silvana Valensin and Stazi, {Maria Antonietta} and Giuseppe Passarino and Luca Deiana and Gonos, {Efstathios S} and Lavinia Paternoster and S{\o}rensen, {Thorkild I A} and Qihua Tan and Quinta Helmer and {van den Akker}, {Erik B} and Joris Deelen and Francesca Martella and Cordell, {Heather J} and Ayers, {Kristin L} and Vaupel, {James W.} and Outi T{\"o}rnwall and Johnson, {Thomas E} and Stefan Schreiber and Mark Lathrop and Axel Skytthe and Westendorp, {Rudi G J} and Kaare Christensen and Jutta Gampe and Almut Nebel and Houwing-Duistermaat, {Jeanine J} and Slagboom, {Pieternella Eline} and Claudio Franceschi and GEHA consortium",

year = "2013",

doi = "10.1111/acel.12039",

language = "English",

volume = "12",

pages = "184--193",

journal = "Aging Cell",

issn = "1474-9718",

publisher = "Wiley-Blackwell",

number = "2",

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TY - JOUR

T1 - Genome-wide linkage analysis for human longevity

T2 - Genetics of Healthy Aging Study

AU - Beekman, Marian

AU - Blanché, Hélène

AU - Perola, Markus

AU - Hervonen, Anti

AU - Bezrukov, Vladyslav

AU - Sikora, Ewa

AU - Christiansen, Lene

AU - Flachsbart, Friederike

AU - De Craen, Anton J M

AU - Kirkwood, Tom B L

AU - Rea, Irene Maeve

AU - Poulain, Michel

AU - Robine, Jean-Marie

AU - Valensin, Silvana

AU - Stazi, Maria Antonietta

AU - Passarino, Giuseppe

AU - Deiana, Luca

AU - Gonos, Efstathios S

AU - Paternoster, Lavinia

AU - Sørensen, Thorkild I A

AU - Tan, Qihua

AU - Helmer, Quinta

AU - van den Akker, Erik B

AU - Deelen, Joris

AU - Martella, Francesca

AU - Cordell, Heather J

AU - Ayers, Kristin L

AU - Vaupel, James W.

AU - Törnwall, Outi

AU - Johnson, Thomas E

AU - Schreiber, Stefan

AU - Lathrop, Mark

AU - Skytthe, Axel

AU - Westendorp, Rudi G J

AU - Christensen, Kaare

AU - Gampe, Jutta

AU - Nebel, Almut

AU - Houwing-Duistermaat, Jeanine J

AU - Slagboom, Pieternella Eline

AU - Franceschi, Claudio

AU - consortium, GEHA

PY - 2013

Y1 - 2013

N2 - Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10-8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10-5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

AB - Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10-8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10-5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

U2 - 10.1111/acel.12039

DO - 10.1111/acel.12039

M3 - Journal article

C2 - 23286790

SN - 1474-9718

VL - 12

SP - 184

EP - 193

JO - Aging Cell

JF - Aging Cell

IS - 2

ER -

Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

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