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

Ian P M Tomlinson, Luis Carvajal-Carmona, Sara E. Dobbins, Albert Tenesa, Angela M. Jones, Kimberley Howarth, Claire Palles, Peter Broderick, Emma E M Jaeger, Susan Farrington, Annabelle Lewis, James G D Prendergast, Alan M. Pittman, Evropi Theodoratou, Bianca Olver, Marion Walker, Steven Penegar, Ella Barclay, Nicola Whiffin, Lynn MartinStephane Ballereau, Amy Lloyd, Maggie Gorman, Steven Lubbe, Bryan Howie, Jonathan Marchini, Clara Ruiz-Ponte, Ceres Fernandez-Rozadilla, Antoni Castells, Angel Carracedo, Sergi Castellvi-Bel, David Duggan, David Conti, Jean Baptiste Cazier, Harry Campbell, Oliver Sieber, Lara Lipton, Peter Gibbs, Nicholas G. Martin, Grant W. Montgomery, Joanne Young, Paul N. Baird, Steven Gallinger, Polly Newcomb, John Hopper, Mark A. Jenkins, Lauri A. Aaltonen, David J. Kerr, Jeremy Cheadle, Paul Pharoah, Graham Casey, Richard S. Houlston, Malcolm G. Dunlop

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere1002105
JournalPLoS Genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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    Tomlinson, I. P. M., Carvajal-Carmona, L., Dobbins, S. E., Tenesa, A., Jones, A. M., Howarth, K., Palles, C., Broderick, P., Jaeger, E. E. M., Farrington, S., Lewis, A., Prendergast, J. G. D., Pittman, A. M., Theodoratou, E., Olver, B., Walker, M., Penegar, S., Barclay, E., Whiffin, N., ... Dunlop, M. 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]. https://doi.org/10.1371/journal.pgen.1002105