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 G. 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 Martin; Stephane 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

doi:10.1371/journal.pgen.1002105

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 G. 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

Neurology

Research output: Contribution to journal › Article › peer-review

183 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 language	English (US)
Article number	e1002105
Journal	PLoS genetics
Volume	7
Issue number	6
DOIs	https://doi.org/10.1371/journal.pgen.1002105
State	Published - Jun 2011

Funding

ASJC Scopus subject areas

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1002105

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Tomlinson, I. P. M., Carvajal-Carmona, L. G., 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), Article e1002105. https://doi.org/10.1371/journal.pgen.1002105

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

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.",

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

year = "2011",

month = jun,

doi = "10.1371/journal.pgen.1002105",

language = "English (US)",

volume = "7",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "6",

}

Tomlinson, IPM, Carvajal-Carmona, LG, 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

TY - JOUR

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 G.

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

AU - Baird, Paul N.

AU - Gallinger, Steven

AU - Newcomb, Polly

AU - Hopper, John

AU - Jenkins, Mark A.

AU - Aaltonen, Lauri A.

AU - Kerr, David J.

AU - Cheadle, Jeremy

AU - Pharoah, Paul

AU - Casey, Graham

AU - Houlston, Richard S.

AU - Dunlop, Malcolm G.

PY - 2011/6

Y1 - 2011/6

N2 - 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.

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

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ASJC Scopus subject areas

UN SDGs

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