A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.
Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.
Tomlinson
Ian
I
Molecular and Population Genetics Laboratory, Cancer Research UK, London WC2A 3PX, UK. ian.tomlinson@cancer.org.uk
Webb
Emily
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Carvajal-Carmona
Luis
L
Broderick
Peter
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Kemp
Zoe
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Spain
Sarah
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Penegar
Steven
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Chandler
Ian
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Gorman
Maggie
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Wood
Wendy
W
Barclay
Ella
E
Lubbe
Steven
S
Martin
Lynn
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Sellick
Gabrielle
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Jaeger
Emma
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Hubner
Richard
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Wild
Ruth
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Rowan
Andrew
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Fielding
Sarah
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Howarth
Kimberley
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Silver
Andrew
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Atkin
Wendy
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Muir
Kenneth
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Logan
Richard
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Kerr
David
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Johnstone
Elaine
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Sieber
Oliver
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Gray
Richard
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Thomas
Huw
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Peto
Julian
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Cazier
Jean-Baptiste
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Houlston
Richard
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D000368:Aged; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide