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

Molecular Epidemiology, Leiden University Medical Centre, Leiden, 2333, ZC, The Netherlands
Aging cell (Impact Factor: 6.34). 01/2013; 12(2). DOI: 10.1111/acel.12039
Source: PubMed


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 fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (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 1,228 unrelated nonagenarian and 1,907 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 x 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 x 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. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Available from: Marian Beekman
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    • "A genome-wide linkage analysis on 2118 European nonagenarian full sibships of the GEHA project was performed to identify chromosomal regions involved in longevity [52]. By using Illumina HumanLinkage12 Genotyping BeadChip, four regions (14q11.2, "
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    • "Interestingly, the GEHA study observed heterogeneity among its multiple geographic regions; Northern European subjects contribute most to some of the linkage peaks they observe, including the APOE locus. Gender-specific effects were also observed, with a male-specific linkage peak at 8p and female-specific ones at 15q and the 19q APOE locus (Beekman et al. 2013). While the lack of association at the other linkage regions in the GEHA study may be due to power limitations, it could also imply that multiple rare or ‘private’ variants contribute to linkage but not association at these loci. "
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