Open AccessGenome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study
Author(s) -
Beekman Marian,
Blanché Hélène,
Perola Markus,
Hervonen Anti,
Bezrukov Vladyslav,
Sikora Ewa,
Flachsbart Friederike,
Christiansen Lene,
Craen Anton J. M.,
Kirkwood Tom B. L.,
Rea Irene Maeve,
Poulain Michel,
Robine JeanMarie,
Valensin Silvana,
Stazi Maria Antonietta,
Passarino Giuseppe,
Deiana Luca,
Gonos Efstathios S.,
Paternoster Lavinia,
Sørensen Thorkild I. A.,
Tan Qihua,
Helmer Quinta,
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 G. J.,
Christensen Kaare,
Gampe Jutta,
Nebel Almut,
HouwingDuistermaat Jeanine J.,
Slagboom Pieternella Eline,
Franceschi Claudio
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12039
Subject(s) - longevity , biology , genetics , locus (genetics) , genetic linkage , genome wide association study , genetic association , allele , gene , single nucleotide polymorphism , genotype
Summary 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 C aucasian sibling pairs that have been enrolled in 15 study centers of 11 E uropean countries as part of the G enetics of H ealthy A ging ( 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 TOMM 40/ APOE / APOC 1 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 APOE ε4 and APOE ε2 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.