Dataset Information

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

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 = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOE?4 and APOE?2 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.

SUBMITTER: Beekman M

PROVIDER: S-EPMC3725963 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Beekman Marian M Blanché Hélène H Perola Markus M Hervonen Anti A Bezrukov Vladyslav V Sikora Ewa E Flachsbart Friederike F Christiansen Lene L De Craen Anton J M AJ Kirkwood Tom B L TB Rea Irene Maeve IM Poulain Michel M Robine Jean-Marie JM Valensin Silvana S Stazi Maria Antonietta MA Passarino Giuseppe G Deiana Luca L Gonos Efstathios S ES Paternoster Lavinia L Sørensen Thorkild I A TI Tan Qihua Q Helmer Quinta Q van den Akker Erik B EB Deelen Joris J Martella Francesca F Cordell Heather J HJ Ayers Kristin L KL Vaupel James W JW Törnwall Outi O Johnson Thomas E TE Schreiber Stefan S Lathrop Mark M Skytthe Axel A Westendorp Rudi G J RG Christensen Kaare K Gampe Jutta J Nebel Almut A Houwing-Duistermaat Jeanine J JJ Slagboom Pieternella Eline PE Franceschi Claudio C

Aging cell 20130206 2

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 s ...[more]

PMID: 23286790

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Project description:Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.

Dataset Information

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

Publications

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

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