Article Dans Une Revue Aging Cell Année : 2013

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

1 LUMC - Leiden University Medical Center [Leiden]
2 CEPH - Fondation Jean Dausset - Centre d’Études du Polymorphisme Humain
3 National Institute for Health and Welfare [Helsinki]
4 Tampere School of Public Health
5 Institute of Gerontology [Kiev]
6 Nencki Institute of Experimental Biology
7 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
8 SDU - University of Southern Denmark = Syddansk Universitet
9 Netherlands Consortium for Healthy Ageing
10 Newcastle University [Newcastle]
11 QUB - Queen's University [Belfast]
12 UCLouvain - Université Catholique de Louvain = Catholic University of Louvain
13 CERMES3 - UMR 8211 / U988 / UM 7 - CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société
14 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna [Bologne]
15 ISS - Istituto Superiore di Sanità = Italian National Institute of Health [Roma, Italia]
16 UniCal - Università della Calabria [Arcavacata di Rende, Italia] = University of Calabria [Italy] = Université de Calabre [Italie]
17 UNISS - Università degli Studi di Sassari = University of Sassari
18 Theoretical and Physical Chemistry Institute NHRF
19 University of Bristol [Bristol]
20 CBMR - Novo Nordisk Foundation Center for Basic Metabolic Research
21 OUH - Odense University Hospital
22 Institute for Ageing and Health, Newcastle University
23 MPIDR - Max Planck Institute for Demographic Research
24 University of Colorado [Boulder]

Résumé

Clear evidence exists for heritability of human longevity, 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 2118 nonagenarian 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=9.6x108). By combined modeling of linkage and association, we showed that association of longevity with APOE epsilon 4 and APOE epsilon 2 alleles explain the linkage at 19q13.11-q13.32 with P-value=0.02 and P-value=1.0x105, 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.

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hal-03478919 , version 1 (24-01-2022)

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M Beekman, H Blanché, M Perola, A Hervonen, V Bezrukov, et al.. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. Aging Cell, 2013, 12 (2), pp.184-93. ⟨10.1111/acel.12039⟩. ⟨hal-03478919⟩
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