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

149 Citations (Scopus)

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

Fingerprint

bone morphogenetic proteins
Bone Morphogenetic Proteins
heritability
colorectal neoplasms
Single Nucleotide Polymorphism
bone
Colorectal Neoplasms
cancer
loci
protein
gene
Genome-Wide Association Study
tagging
single nucleotide polymorphism
polymorphism
genes
genome
Genes
penetrance
Penetrance

ASJC Scopus subject areas

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

Cite this

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; 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.

In: PLoS Genetics, Vol. 7, No. 6, e1002105, 06.2011.

Research output: Contribution to journalArticle

Tomlinson, IPM, Carvajal-Carmona, L, Dobbins, SE, Tenesa, A, Jones, AM, Howarth, K, Palles, C, Broderick, P, Jaeger, EEM, Farrington, S, Lewis, A, Prendergast, JGD, Pittman, AM, Theodoratou, E, Olver, B, Walker, M, Penegar, S, Barclay, E, Whiffin, N, Martin, L, Ballereau, S, Lloyd, A, Gorman, M, Lubbe, S, Howie, B, Marchini, J, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Castells, A, Carracedo, A, Castellvi-Bel, S, Duggan, D, Conti, D, Cazier, JB, Campbell, H, Sieber, O, Lipton, L, Gibbs, P, Martin, NG, Montgomery, GW, Young, J, Baird, PN, Gallinger, S, Newcomb, P, Hopper, J, Jenkins, MA, Aaltonen, LA, Kerr, DJ, Cheadle, J, Pharoah, P, Casey, G, Houlston, RS & Dunlop, MG 2011, 'Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer', PLoS Genetics, vol. 7, no. 6, e1002105. https://doi.org/10.1371/journal.pgen.1002105
Tomlinson, Ian P M ; Carvajal-Carmona, Luis ; 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. In: PLoS Genetics. 2011 ; Vol. 7, No. 6.
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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.",
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T1 - Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer

AU - Tomlinson, Ian P M

AU - Carvajal-Carmona, Luis

AU - Dobbins, Sara E.

AU - Tenesa, Albert

AU - Jones, Angela M.

AU - Howarth, Kimberley

AU - Palles, Claire

AU - Broderick, Peter

AU - Jaeger, Emma E M

AU - Farrington, Susan

AU - Lewis, Annabelle

AU - Prendergast, James G D

AU - Pittman, Alan M.

AU - Theodoratou, Evropi

AU - Olver, Bianca

AU - Walker, Marion

AU - Penegar, Steven

AU - Barclay, Ella

AU - Whiffin, Nicola

AU - Martin, Lynn

AU - Ballereau, Stephane

AU - Lloyd, Amy

AU - Gorman, Maggie

AU - Lubbe, Steven

AU - Howie, Bryan

AU - Marchini, Jonathan

AU - Ruiz-Ponte, Clara

AU - Fernandez-Rozadilla, Ceres

AU - Castells, Antoni

AU - Carracedo, Angel

AU - Castellvi-Bel, Sergi

AU - Duggan, David

AU - Conti, David

AU - Cazier, Jean Baptiste

AU - Campbell, Harry

AU - Sieber, Oliver

AU - Lipton, Lara

AU - Gibbs, Peter

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Young, Joanne

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AU - Jenkins, Mark A.

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AU - Houlston, Richard S.

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