PMID- 23286790 OWN - NLM STAT- MEDLINE DCOM- 20130827 LR - 20220129 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 12 IP - 2 DP - 2013 Apr TI - Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. PG - 184-93 LID - 10.1111/acel.12039 [doi] AB - 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 x 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEepsilon4 and APOEepsilon2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 x 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. CI - (c) 2013 The Authors Aging Cell (c) 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. FAU - Beekman, Marian AU - Beekman M AD - Molecular Epidemiology, Leiden University Medical Centre, Leiden, ZC, 2333, The Netherlands. m.beekman@lumc.nl FAU - Blanche, Helene AU - Blanche H FAU - Perola, Markus AU - Perola M FAU - Hervonen, Anti AU - Hervonen A FAU - Bezrukov, Vladyslav AU - Bezrukov V FAU - Sikora, Ewa AU - Sikora E FAU - Flachsbart, Friederike AU - Flachsbart F FAU - Christiansen, Lene AU - Christiansen L FAU - De Craen, Anton J M AU - De Craen AJ FAU - Kirkwood, Tom B L AU - Kirkwood TB FAU - Rea, Irene Maeve AU - Rea IM FAU - Poulain, Michel AU - Poulain M FAU - Robine, Jean-Marie AU - Robine JM FAU - Valensin, Silvana AU - Valensin S FAU - Stazi, Maria Antonietta AU - Stazi MA FAU - Passarino, Giuseppe AU - Passarino G FAU - Deiana, Luca AU - Deiana L FAU - Gonos, Efstathios S AU - Gonos ES FAU - Paternoster, Lavinia AU - Paternoster L FAU - Sorensen, Thorkild I A AU - Sorensen TI FAU - Tan, Qihua AU - Tan Q FAU - Helmer, Quinta AU - Helmer Q FAU - van den Akker, Erik B AU - van den Akker EB FAU - Deelen, Joris AU - Deelen J FAU - Martella, Francesca AU - Martella F FAU - Cordell, Heather J AU - Cordell HJ FAU - Ayers, Kristin L AU - Ayers KL FAU - Vaupel, James W AU - Vaupel JW FAU - Tornwall, Outi AU - Tornwall O FAU - Johnson, Thomas E AU - Johnson TE FAU - Schreiber, Stefan AU - Schreiber S FAU - Lathrop, Mark AU - Lathrop M FAU - Skytthe, Axel AU - Skytthe A FAU - Westendorp, Rudi G J AU - Westendorp RG FAU - Christensen, Kaare AU - Christensen K FAU - Gampe, Jutta AU - Gampe J FAU - Nebel, Almut AU - Nebel A FAU - Houwing-Duistermaat, Jeanine J AU - Houwing-Duistermaat JJ FAU - Slagboom, Pieternella Eline AU - Slagboom PE FAU - Franceschi, Claudio AU - Franceschi C CN - GEHA consortium LA - eng GR - R01 EY018246/EY/NEI NIH HHS/United States GR - MR/J012165/1/MRC_/Medical Research Council/United Kingdom GR - R01 EY014685/EY/NEI NIH HHS/United States GR - Wellcome Trust/United Kingdom GR - P01-AG08761/AG/NIA NIH HHS/United States GR - P01 AG008761/AG/NIA NIH HHS/United States GR - G20234/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130206 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (APOC1 protein, human) RN - 0 (Apolipoprotein C-I) RN - 0 (Apolipoproteins E) RN - 0 (Membrane Transport Proteins) RN - 0 (Mitochondrial Precursor Protein Import Complex Proteins) RN - 0 (TOMM40 protein, human) SB - IM MH - Aged MH - Aged, 80 and over MH - Alleles MH - Apolipoprotein C-I/*genetics MH - Apolipoproteins E/*genetics MH - Chromosome Mapping MH - Chromosomes, Human, Pair 14 MH - Chromosomes, Human, Pair 17 MH - Chromosomes, Human, Pair 19 MH - Cluster Analysis MH - Europe MH - Genetic Linkage MH - *Genetic Loci MH - Genome, Human MH - Genome-Wide Association Study MH - Humans MH - Lod Score MH - Longevity/*genetics MH - Membrane Transport Proteins/*genetics MH - Middle Aged MH - Mitochondrial Precursor Protein Import Complex Proteins MH - Siblings PMC - PMC3725963 MID - NIHMS430189 EDAT- 2013/01/05 06:00 MHDA- 2013/08/28 06:00 PMCR- 2014/04/01 CRDT- 2013/01/05 06:00 PHST- 2012/11/27 00:00 [accepted] PHST- 2013/01/05 06:00 [entrez] PHST- 2013/01/05 06:00 [pubmed] PHST- 2013/08/28 06:00 [medline] PHST- 2014/04/01 00:00 [pmc-release] AID - 10.1111/acel.12039 [doi] PST - ppublish SO - Aging Cell. 2013 Apr;12(2):184-93. doi: 10.1111/acel.12039. Epub 2013 Feb 6.