TY - JOUR
T1 - Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited
AU - Deelen, J
AU - Beekman, M
AU - Uh, HW
AU - Helmer, Q
AU - Kuningas, Maris
AU - Christiansen, L
AU - Kremer, D
AU - van der Breggen, R
AU - Suchiman, HED
AU - Lakenberg, N
AU - van den Akker, EB
AU - Passtoors, WM
AU - Tiemeier, Henning
AU - van Heemst, D
AU - de Craen, AJ
AU - Rivadeneira, Fernando
AU - de Geus, EJ
AU - Perola, M
AU - van der Ouderaa, FJ
AU - Gunn, DA
AU - Boomsma, DI
AU - Uitterlinden, André
AU - Christensen, K
AU - Duijn, Cornelia
AU - Heijmans, BT (Bastiaan)
AU - Houwing-Duistermaat, JJ
AU - Westendorp, RGJ
AU - Slagboom, PE (Eline)
PY - 2011
Y1 - 2011
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 x 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 x 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 epsilon 4 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 epsilon 4 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 x 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 x 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 epsilon 4 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 epsilon 4 allele. No other major longevity locus was found.
U2 - 10.1111/j.1474-9726.2011.00705.x
DO - 10.1111/j.1474-9726.2011.00705.x
M3 - Article
SN - 1474-9718
VL - 10
SP - 686
EP - 698
JO - Aging Cell
JF - Aging Cell
IS - 4
ER -