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

Beekman, Marian

Blanché, Hélène

Perola, Markus

Hervonen, Anti

Bezrukov, Vladyslav

Sikora, Ewa

Flachsbart, Friederike

Christiansen, Lene

De Craen, Anton JM

Kirkwood, Tom BL

Rea, Irene Maeve

Poulain, Michel

Robine, Jean-Marie

Valensin, Silvana

Stazi, Maria Antonietta

Passarino, Giuseppe

Deiana, Luca

Gonos, Efstathios S

Paternoster, Lavinia

Sørensen, Thorkild IA

Tan, Qihua

Helmer, Quinta

van den Akker, Erik B

Deelen, Joris

Martella, Francesca

Cordell, Heather J

Ayers, Kristin L

Vaupel, James W

Törnwall, Outi

Johnson, Thomas E

Schreiber, Stefan

Lathrop, Mark

Skytthe, Axel

Westendorp, Rudi GJ

Christensen, Kaare

Gampe, Jutta

Nebel, Almut

Houwing-Duistermaat, Jeanine J

Slagboom, Pieternella Eline

Franceschi, Claudio

GEHA consortium

England

2017-06-01T20:12:59Z

2017-06-01T20:12:59Z

2013-04

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.

https://www.ncbi.nlm.nih.gov/pubmed/23286790

1474-9726

https://hdl.handle.net/10161/14718

eng

Wiley

Aging Cell

10.1111/acel.12039

Aged

Aged, 80 and over

Alleles

Apolipoprotein C-I

Apolipoproteins E

Chromosome Mapping

Chromosomes, Human, Pair 14

Chromosomes, Human, Pair 17

Chromosomes, Human, Pair 19

Cluster Analysis

Europe

Genetic Linkage

Genetic Loci

Genome, Human

Genome-Wide Association Study

Humans

Lod Score

Longevity

Membrane Transport Proteins

Middle Aged

Siblings

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

Journal article

https://www.ncbi.nlm.nih.gov/pubmed/23286790

184

193

2

Center for Population Health & Aging

Duke

Duke Population Research Institute

Sanford School of Public Policy

Published

12