title: A novel sampling design to explore gene-longevity associations: the ECHA study.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Calabria, Rende, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Rango
authors.forename: Serena
authors.initials: S
authors.lastname: Dato
authors.forename: Dina
authors.initials: D
authors.lastname: Bellizzi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rose
authors.forename: Erika
authors.initials: E
authors.lastname: Marzi
authors.forename: Luca
authors.initials: L
authors.lastname: Cavallone
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.forename: Axel
authors.initials: A
authors.lastname: Skytthe
authors.forename: Bernard
authors.initials: B
authors.lastname: Jeune
authors.forename: Amandine
authors.initials: A
authors.lastname: Cournil
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Robine
authors.forename: Jutta
authors.initials: J
authors.lastname: Gampe
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mari
authors.forename: Emidio
authors.initials: E
authors.lastname: Feraco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Andrea
authors.initials: A
authors.lastname: Novelletto
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Benedictis
mesh_terms: 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