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

M Beekman 1 H Blanché 2 M Perola 3 A Hervonen 4 V Bezrukov 5 E Sikora 6 F Flachsbart 7 L Christiansen 8 Ajm de Craen 9, 1 Tb Kirkwood 10 Im Rea 11 M Poulain 12 Jean-Marie Robine 13 S Valensin 14 Ma Stazi 15 G Passarino 16 L Deiana 17 Es Gonos 18 L Paternoster 19 Ti Sørensen 20 Q Tan 8, 21 Q Helmer 1 Eb van den Akker 1 J Deelen 1 F Martella 1 Hj Cordell 22 Kl Ayers 22, 10 Jw Vaupel 23 O Törnwall 3 Te Johnson 24 S Schreiber 7 M Lathrop 2 A Skytthe 8 Rg Westendorp 1 K Christensen 8, 21 J Gampe 23 A Nebel 7 Jj Houwing-Duistermaat 9, 1 Pe Slagboom 1, 9 C Franceschi 14 
Abstract : 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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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, Blackwell Publishing Ltd, 2013, 12 (2), pp.184-93. ⟨10.1111/acel.12039⟩. ⟨hal-03478919⟩

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