A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3


Tomlinson, IPM; Webb, E; Carvajal-Carmona, L; Broderick, P; Howarth, K; Pittman, AM; Spain, S; Lubbe, S; Walther, A; Sullivan, K; Jaeger, E; Fielding, S; Rowan, A; Vijayakrishnan, J; Domingo, E; Chandler, I; Kemp, Z; Qureshi, M; Farrington, SM; Tenesa, A; Prendergast, JGD; Barnetson, RA; Penegar, S; Barclay, E; Wood, W; Martin, L; Gorman, M; Thomas, H; Peto, J; Bishop, DT; Gray, R; Maher, ER; Lucassen, A; Kerr, D; Evans, DGR; Schafmayer, C; Buch, S; Volzke, H; Hampe, J; Schreiber, S; John, U; Koessler, T; Pharoah, P; van Wezel, T; Morreau, H; Wijnen, JT; Hopper, JL; Southey, MC; Giles, GG; Severi, G; Castellvi-Bel, S; Ruiz-Ponte, C; Carracedo, A; Castells, A; Forsti, A; Hemminki, K; Vodicka, P; Naccarati, A; Lipton, L; Ho, JWC; Cheng, KK; Sham, PC; Luk, J; Agundez, JAG; Ladero, JM; de la Hoya, M; Caldes, T; Niittymaeki, I; Tuupanen, S; Karhu, A; Aaltonen, L; Cazier, JB; Campbell, H; Dunlop, MG; Houlston, RS; (2008) A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature genetics, 40 (5). pp. 623-630. ISSN 1061-4036 DOI: https://doi.org/10.1038/ng.111

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Abstract

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping ( 10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P=2.5 x 10(-13) overall; P=6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P=3.3 x 10(-18) overall; P=9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

Item Type: Article
Keywords: PROSTATE-CANCER, BREAST-CANCER, RISK, METAANALYSIS, VARIANT, EIF3S3, TUMORS, GENES, SCAN, Adult, Aged, Alleles, Chromosomes, Human, Pair 10, genetics, Chromosomes, Human, Pair 8, genetics, Colorectal Neoplasms, genetics, Eukaryotic Initiation Factor-3, genetics, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Linkage (Genetics), Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 18372905
Web of Science ID: 255366700031
URI: http://researchonline.lshtm.ac.uk/id/eprint/7584

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