TY - JOUR
T1 - Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited
AU - Deelen, Joris
AU - Beekman, Marian
AU - Uh, Hae Won
AU - Helmer, Quinta
AU - Kuningas, Maris
AU - Christiansen, Lene
AU - Kremer, Dennis
AU - van der Breggen, Ruud
AU - Suchiman, H. Eka D.
AU - Lakenberg, Nico
AU - van den Akker, Erik B.
AU - Passtoors, Willemijn M.
AU - Tiemeier, Henning
AU - van Heemst, Diana
AU - de Craen, Anton J.
AU - Rivadeneira, Fernando
AU - de Geus, Eco J.
AU - Perola, Markus
AU - van der Ouderaa, Frans J.
AU - Gunn, David A.
AU - Boomsma, Dorret I.
AU - Uitterlinden, André G.
AU - Christensen, Kaare
AU - van Duijn, Cornelia M.
AU - Heijmans, Bastiaan T.
AU - Houwing-Duistermaat, Jeanine J.
AU - Westendorp, Rudi G.J.
AU - Slagboom, P. Eline
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
KW - Aging
KW - Apolipoprotein E
KW - Genetics
KW - Genome-wide association study
KW - Human
KW - Longevity
UR - http://www.scopus.com/inward/record.url?scp=79960304808&partnerID=8YFLogxK
U2 - 10.1111/j.1474-9726.2011.00705.x
DO - 10.1111/j.1474-9726.2011.00705.x
M3 - Article
C2 - 21418511
AN - SCOPUS:79960304808
SN - 1474-9718
VL - 10
SP - 686
EP - 698
JO - Aging Cell
JF - Aging Cell
IS - 4
ER -