Journal
AGING CELL
Volume 12, Issue 2, Pages 184-193Publisher
WILEY
DOI: 10.1111/acel.12039
Keywords
APOE gene; association analysis; genome-wide linkage analysis; Human familial longevity; nonagenarian sibling pairs
Categories
Funding
- EU GEHA Project [LSHM-CT-2004-503-270]
- Competitive Research Funding of the Tampere University Hospital (Tampere)
- Academy of Finland (Tampere)
- United States National Institute of Aging (Odense) [PO1-AG08761]
- Innovation Oriented Research Program on Genomics [Senter-Novem IGE05007]
- Centre for Medical Systems Biology (CMSB)
- National Institute for Healthy Ageing [NCHA 05060810]
- Institute for Ageing and Health
- UK NIHR Biomedical Research Centre for Ageing and Age-related disease
- European Union [259679]
- Wellcome Trust
- European Community [HEALTH-F2-2008-201865 GEFOS, HEALTH-F4-2007-201413 ENGAGE]
- FP5 Programme (GenomEUtwin Project) [QLG2-CT-2002-01254]
- BBSRC project [G20234]
- National Eye Institute via an NIH/CIDR genotyping project
- MRC [MR/J012165/1] Funding Source: UKRI
- Medical Research Council [G0700718B, MR/J012165/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10260] Funding Source: researchfish
Ask authors/readers for more resources
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=9.6x108). By combined modeling of linkage and association, we showed that association of longevity with APOE epsilon 4 and APOE epsilon 2 alleles explain the linkage at 19q13.11-q13.32 with P-value=0.02 and P-value=1.0x105, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available