Open AccessDeciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer
Author(s) -
Nicola Whiffin,
Sara E. Dobbins,
Fay J. Hosking,
Claire Palles,
Albert Tenesa,
Yufei Wang,
Susan M. Farrington,
Angela Jones,
Peter Broderick,
Harry Campbell,
Polly A. Newcomb,
Graham Casey,
David V. Conti,
Fredrick Schumacher,
Steve Gallinger,
Noralane M. Lindor,
John L. Hopper,
Mark A. Jenkins,
Malcolm G. Dunlop,
Ian Tomlinson,
Richard S. Houlston
Publication year - 2013
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddt357
Subject(s) - linkage disequilibrium , imputation (statistics) , genome wide association study , genetic association , penetrance , biology , genetic architecture , genetics , computational biology , genotype , quantitative trait locus , computer science , single nucleotide polymorphism , gene , missing data , phenotype , machine learning
Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant.