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Author:
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Picelli, Simone; Bermejo, Justo Lorenzo; Chang-Claude, Jenny; Hoffmeister, Michael; Fernández-Rozadilla, Ceres; Carracedo, Angel; Castells, Antoni; Castellví-Bel, Sergi; Naccarati, Alessio; Pardini, Barbara; Vodickova, Ludmila; Müller, Heiko; Talseth-Palmer, Bente A.; Stibbard, Geoffrey; Peterlongo, Paolo; Nici, Carmela; Veneroni, Silvia; Li, Li; Casey, Graham; Tenesa, Albert; Farrington, Susan M.; Tomlinson, Ian; Moreno, Victor; Van Wezel, Tom; Wijnen, Juul; Dunlop, Malcolm; Radice, Paolo; Scott, Rodney J.; Vodicka, Pavel; Ruiz-Ponte, Clara; Brenner, Hermann; Buch, Stephan; Völzke, Henry; Hampe, Jochen; Schafmayer, Clemens; Lindblom, Annika
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Notes:
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In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on
fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants,
most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a
case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a followup
of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on
eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for
one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish
replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided
to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000
cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate
the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental
exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects
between Sweden and the other investigated cohorts. |
