Open AccessGenome‐wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited
Author(s) -
Deelen Joris,
Beekman Marian,
Uh HaeWon,
Helmer Quinta,
Kuningas Maris,
Christiansen Lene,
Kremer Dennis,
van der Breggen Ruud,
Suchiman H. Eka D.,
Lakenberg Nico,
van den Akker Erik B.,
Passtoors Willemijn M.,
Tiemeier Henning,
van Heemst Diana,
de Craen Anton J.,
Rivadeneira Fernando,
de Geus Eco J,
Perola Markus,
van der Ouderaa Frans J.,
Gunn David A.,
Boomsma Dorret I.,
Uitterlinden André G.,
Christensen Kaare,
van Duijn Cornelia M.,
Heijmans Bastiaan T.,
HouwingDuistermaat Jeanine J.,
Westendorp Rudi G. J.,
Slagboom P. Eline
Publication year - 2011
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/j.1474-9726.2011.00705.x
Subject(s) - genome wide association study , linkage disequilibrium , locus (genetics) , single nucleotide polymorphism , snp , biology , apolipoprotein e , longevity , genetics , genetic association , allele , population , medicine , gene , genotype , disease , environmental health
Summary By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome‐wide association study (GWAS) comparing 403 unrelated nonagenarians from long‐living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta‐analysis of nonagenarian cases from the Rotterdam Study, Leiden 85‐plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis ( P < 1 × 10 −4 ) showed genome‐wide significance with survival into old age in the meta‐analysis of 4149 nonagenarian cases and 7582 younger controls [OR = 0.71 (95% CI 0.65–0.77), P = 3.39 × 10 −17 ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E ( APOE ) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE ‐independent effect of rs2075650 on longevity, either in cross‐sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF‐1 in women ( P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.