Genome-wide linkage analysis for human longevity: Genetics of healthy aging study

Marian Beekman, Hélène Blanché, Markus Perola, Anti Hervonen, Vladyslav Bezrukov, Ewa Sikora, Friederike Flachsbart, Lene Christiansen, Anton J. M. De Craen, Tom B. L. Kirkwood, 1 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, Kristen 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

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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). 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, 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 languageEnglish
Pages (from-to)184-193
Number of pages10
JournalAging cell
Volume12
Issue number2
Early online date06 Feb 2013
DOIs
Publication statusPublished - Apr 2013
EventSuper Vivere Exhbition - Naughton Gallery, Queens University Belfast, Belfast, United Kingdom
Duration: 07 Jan 201126 Mar 2011

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