title: Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
abstract: 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 = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , 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.affiliation: Molecular Epidemiology, Leiden University Medical Centre, Leiden, ZC, 2333, The Netherlands. m.beekman@lumc.nl
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authors.lastname: Beekman
authors.forename: Hélène
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authors.lastname: Blanché
authors.forename: Markus
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authors.forename: Anti
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authors.forename: Vladyslav
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authors.forename: Maria Antonietta
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authors.lastname: Gonos
authors.forename: Lavinia
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authors.lastname: Paternoster
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authors.forename: Qihua
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authors.lastname: Tan
authors.forename: Quinta
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authors.lastname: Helmer
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authors.initials: EB
authors.lastname: van den Akker
authors.forename: Joris
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authors.lastname: Deelen
authors.forename: Francesca
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authors.lastname: Martella
authors.forename: Heather J
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authors.lastname: Cordell
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Ayers
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.forename: Outi
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authors.lastname: Törnwall
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authors.lastname: Johnson
authors.forename: Stefan
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authors.lastname: Schreiber
authors.forename: Mark
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authors.lastname: Lathrop
authors.forename: Axel
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authors.lastname: Skytthe
authors.forename: Rudi G J
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authors.lastname: Westendorp
authors.forename: Kaare
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authors.lastname: Christensen
authors.forename: Jutta
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authors.lastname: Gampe
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Pieternella Eline
authors.initials: PE
authors.lastname: Slagboom
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authors.lastname: Franceschi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D053302:Apolipoprotein C-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D016000:Cluster Analysis; D005060:Europe; D008040:Genetic Linkage; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008126:Lod Score; D008136:Longevity / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D035781:Siblings
chemical_list: C505803:APOC1 protein, human; D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human