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

Lookup NU author(s): Emeritus Professor Thomas Kirkwood, Professor Heather Cordell, Dr Kristin Ayers

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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.

Publication metadata

Author(s): Beekman M, Blanche H, Perola M, Hervonen A, Bezrukov V, Sikora E, Flachsbart F, Christiansen L, De Craen AJM, Kirkwood TBL, Rea IM, Poulain M, Robine JM, Valensin S, Stazi MA, Passarino G, Deiana L, Gonos ES, Paternoster L, Sorensen TIA, Tan QH, Helmer Q, van den Akker EB, Deelen J, Martella F, Cordell HJ, Ayers KL, Vaupel JW, Tornwall O, Johnson TE, Schreiber S, Lathrop M, Skytthe A, Westendorp RGJ, Christensen K, Gampe J, Nebel A, Houwing-Duistermaat JJ, Slagboom PE, Franceschi C, GEHA Consortium

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2013

Volume: 12

Issue: 2

Pages: 184-193

Print publication date: 06/02/2013

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/acel.12039

DOI: 10.1111/acel.12039

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