Beekman, Marian3; Blanché, Hélène3; Perola, Markus3; Hervonen, Anti3; Bezrukov, Vladyslav3; Sikora, Ewa3; Christiansen, Lene3; Flachsbart, Friederike3; De Craen, Anton J M3; Kirkwood, Tom B L3; Rea, Irene Maeve3; Poulain, Michel3; Robine, Jean-Marie3; Valensin, Silvana3; Stazi, Maria Antonietta3; Passarino, Giuseppe3; Deiana, Luca3; Gonos, Efstathios S3; Paternoster, Lavinia3; Sørensen, Thorkild I A4; Tan, Qihua3; Helmer, Quinta3; van den Akker, Erik B3; Deelen, Joris3; Martella, Francesca3; Cordell, Heather J3; Ayers, Kristin L3; Vaupel, James W.3; Törnwall, Outi3; Johnson, Thomas E3; Schreiber, Stefan3; Lathrop, Mark3; Skytthe, Axel3; Westendorp, Rudi G J3; Christensen, Kaare3; Gampe, Jutta3; Nebel, Almut3; Houwing-Duistermaat, Jeanine J3; Slagboom, Pieternella Eline3; Franceschi, Claudio3; consortium, GEHA3
1 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
Genetics of Healthy Aging Study
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 = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 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.