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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

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 G...

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Autores principales: 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, Pharoah, Paul, Casey, Graham, Houlston, Richard S., Dunlop, Malcolm G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107194/
https://www.ncbi.nlm.nih.gov/pubmed/21655089
http://dx.doi.org/10.1371/journal.pgen.1002105
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author 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
Pharoah, Paul
Casey, Graham
Houlston, Richard S.
Dunlop, Malcolm G.
author_facet 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
Pharoah, Paul
Casey, Graham
Houlston, Richard S.
Dunlop, Malcolm G.
author_sort Tomlinson, Ian P. M.
collection PubMed
description 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.
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spelling pubmed-31071942011-06-08 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 Pharoah, Paul Casey, Graham Houlston, Richard S. Dunlop, Malcolm G. PLoS Genet Research Article 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. Public Library of Science 2011-06-02 /pmc/articles/PMC3107194/ /pubmed/21655089 http://dx.doi.org/10.1371/journal.pgen.1002105 Text en Tomlinson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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
Pharoah, Paul
Casey, Graham
Houlston, Richard S.
Dunlop, Malcolm G.
Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title_full Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title_fullStr Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title_full_unstemmed Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title_short Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
title_sort multiple common susceptibility variants near bmp pathway loci grem1, bmp4, and bmp2 explain part of the missing heritability of colorectal cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107194/
https://www.ncbi.nlm.nih.gov/pubmed/21655089
http://dx.doi.org/10.1371/journal.pgen.1002105
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