title: BMP2/BMP4 colorectal cancer susceptibility loci in northern and southern European populations.
abstract: Genome-wide association studies have successfully identified 20 colorectal cancer susceptibility loci. Amongst these, four of the signals are defined by tagging single nucleotide polymorphisms (SNPs) on regions 14q22.2 (rs4444235 and rs1957636) and 20p12.3 (rs961253 and rs4813802). These markers are located close to two of the genes involved in bone morphogenetic protein (BMP) signaling (BMP4 and BMP2, respectively). By investigating these four SNPs in an initial cohort of Spanish origin, we found substantial evidence that minor allele frequencies (MAFs) may be different in northern and southern European populations. Therefore, we genotyped three additional southern European cohorts comprising a total of 2028 cases and 4273 controls. The meta-analysis results show that only one of the association signals (rs961253) is effectively replicated in the southern European populations, despite adequate power to detect all four. The other three SNPs (rs4444235, rs1957636 and rs4813802) presented discordant results in MAFs and linkage disequilibrium patterns between northern and southern European cohorts. We hypothesize that this lack of replication could be the result of differential tagging of the functional variant in both sets of populations. Were this true, it would have complex consequences in both our ability to understand the nature of the real causative variants, as well as for further study designs.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-Grupo de Medicina Xenómica-Centro de Investigación Biomédica en Red de Enfermedades Raras-IDIS, Santiago de Compostela 15706, Spain.
authors.forename: Ceres
authors.initials: C
authors.lastname: Fernandez-Rozadilla
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal-Carmona
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Carmela
authors.initials: C
authors.lastname: Nici
authors.forename: Silvia
authors.initials: S
authors.lastname: Veneroni
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Lamas
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: L A
authors.initials: LA
authors.lastname: Lopez-Fernandez
authors.forename: Dolors
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Brea-Fernandez
authors.forename: Juan
authors.initials: J
authors.lastname: Clofent
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.forename: Xavier
authors.initials: X
authors.lastname: Bessa
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.forename: Rosa
authors.initials: R
authors.lastname: Xicola
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellvi-Bel
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005060:Europe / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4