title: Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.
abstract: 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.
authors.affiliation: Section of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.forename: Hae-Won
authors.initials: HW
authors.lastname: Uh
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.forename: Maris
authors.initials: M
authors.lastname: Kuningas
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.forename: Dennis
authors.initials: D
authors.lastname: Kremer
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.forename: Nico
authors.initials: N
authors.lastname: Lakenberg
authors.forename: Erik B
authors.initials: EB
authors.lastname: van den Akker
authors.forename: Willemijn M
authors.initials: WM
authors.lastname: Passtoors
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
authors.forename: Anton J
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Frans J
authors.initials: FJ
authors.lastname: van der Ouderaa
authors.forename: David A
authors.initials: DA
authors.lastname: Gunn
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt