TY - JOUR
T1 - Genome-wide linkage analysis for human longevity
T2 - Genetics of healthy aging study
AU - Beekman, Marian
AU - Blanché, Hélène
AU - Perola, Markus
AU - Hervonen, Anti
AU - Bezrukov, Vladyslav
AU - Sikora, Ewa
AU - Flachsbart, Friederike
AU - Christiansen, Lene
AU - De Craen, Anton J M
AU - Kirkwood, Tom B L
AU - Rea, Irene Maeve
AU - Poulain, Michel
AU - Robine, Jean Marie
AU - Valensin, Silvana
AU - Stazi, Maria Antonietta
AU - Passarino, Giuseppe
AU - Deiana, Luca
AU - Gonos, Efstathios S.
AU - Paternoster, Lavinia
AU - Sørensen, Thorkild I A
AU - Tan, Qihua
AU - Helmer, Quinta
AU - Van Den Akker, Erik B.
AU - Deelen, Joris
AU - Martella, Francesca
AU - Cordell, Heather J.
AU - Ayers, Kristin L.
AU - Vaupel, James W.
AU - Törnwall, Outi
AU - Johnson, Thomas E.
AU - Schreiber, Stefan
AU - Lathrop, Mark
AU - Skytthe, Axel
AU - Westendorp, Rudi G J
AU - Christensen, Kaare
AU - Gampe, Jutta
AU - Nebel, Almut
AU - Houwing-Duistermaat, Jeanine J.
AU - Slagboom, Pieternella Eline
AU - Franceschi, Claudio
PY - 2013
Y1 - 2013
N2 - Clear evidence exists for heritability of humanlongevity, 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 2118nonagenarian 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 APOEe4 and APOEe2 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.
AB - Clear evidence exists for heritability of humanlongevity, 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 2118nonagenarian 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 APOEe4 and APOEe2 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.
KW - Apoe gene
KW - Association analysis
KW - Genome-wide linkage analysis
KW - Human familial longevity
KW - Nonagenarian sibling pairs
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U2 - 10.1111/acel.12039
DO - 10.1111/acel.12039
M3 - Article
C2 - 23286790
AN - SCOPUS:84878933045
VL - 12
SP - 184
EP - 193
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 2
ER -