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Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer

Tomlinson, Ian P. M., Carvajal-Carmona, Luis G., Dobbins, Sara E., Tenesa, Albert, Jones, Angela M., Howarth, Kimberley, Palles, Claire, Broderick, Peter, Jaeger, Emma E. M., Farrington, Susan, Lewis, Annabelle, Prendergast, James G. D., Pittman, Alan M., Theodoratou, Evropi, Olver, Bianca, Walker, Marion, Penegar, Steven, Barclay, Ella, Whiffin, Nicola, Martin, Lynn, Ballereau, Stephane, Lloyd, Amy, Gorman, Maggie, Lubbe, Steven, Howie, Bryan, Marchini, Jonathan, Ruiz-Ponte, Clara, Fernandez-Rozadilla, Ceres, Castells, Antoni, Carracedo, Angel, Castellvi-Bel, Sergi, Duggan, David, Conti, David, Cazier, Jean-Baptiste, Campbell, Harry, Sieber, Oliver, Lipton, Lara, Gibbs, Peter, Martin, Nicholas G., Montgomery, Grant W., Young, Joanne, Baird, Paul N., Gallinger, Steven, Newcomb, Polly, Hopper, John, Jenkins, Mark A., Aaltonen, Lauri A., Kerr, David J., Cheadle, Jeremy Peter, Pharoah, Paul, Casey, Graham, Houlston, Richard S. and Dunlop, Malcolm G. 2011. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genetics 7 (6) , e1002105. 10.1371/journal.pgen.1002105

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Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10−10) and BMP2 (rs4813802, P = 4.65×10−11). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10−8) and rs11632715 (P = 2.30×10−10). As low-penetrance predisposition variants become harder to identify—owing to small effect sizes and/or low risk allele frequencies—approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Public Library of Science
ISSN: 1553-7404
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:53

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