A novel sampling design to explore gene-longevity associations: the ECHA study.
To investigate the genetic contribution to familial similarity in longevity, we set up a novel experimental design where cousin-pairs born from siblings who were concordant or discordant for the longevity trait were analyzed. To check this design, two chromosomal regions already known to encompass longevity-related genes were examined: 6p21.3 (genes TNFalpha, TNFbeta, HSP70.1) and 11p15.5 (genes SIRT3, HRAS1, IGF2, INS, TH). Population pools of 1.6, 2.3 and 2.0 million inhabitants were screened, respectively, in Denmark, France and Italy to identify families matching the design requirements. A total of 234 trios composed by one centenarian, his/her child and a child of his/her concordant or discordant sib were collected. By using population-specific allele frequencies, we reconstructed haplotype phase and estimated the likelihood of Identical By Descent (IBD) haplotype sharing in cousin-pairs born from concordant and discordant siblings. In addition, we analyzed haplotype transmission from centenarians to offspring, and a statistically significant Transmission Ratio Distortion (TRD) was observed for both chromosomal regions in the discordant families (P=0.007 for 6p21.3 and P=0.015 for 11p15.5). In concordant families, a marginally significant TRD was observed at 6p21.3 only (P=0.06). Although no significant difference emerged between the two groups of cousin-pairs, our study gave new insights on the hindrances to recruiting a suitable sample to obtain significant IBD data on longevity-related chromosomal regions. This will allow to dimension future sampling campaigns to study-genetic basis of human longevity.
De Rango
Francesco
F
Department of Cell Biology, University of Calabria, Rende, Italy.
Dato
Serena
S
Bellizzi
Dina
D
Rose
Giuseppina
G
Marzi
Erika
E
Cavallone
Luca
L
Franceschi
Claudio
C
Skytthe
Axel
A
Jeune
Bernard
B
Cournil
Amandine
A
Robine
Jean Marie
JM
Gampe
Jutta
J
Vaupel
James W
JW
Mari
Vincenzo
V
Feraco
Emidio
E
Passarino
Giuseppe
G
Novelletto
Andrea
A
De Benedictis
Giovanna
G
D000368:Aged; D000369:Aged, 80 and over; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003718:Denmark; D005260:Female; D005602:France; D005787:Gene Frequency; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012107:Research Design; D035781:Siblings