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 - COGENT Consortium
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.
KW - Aged
KW - Bone Morphogenetic Protein 2
KW - Bone Morphogenetic Protein 4
KW - Case-Control Studies
KW - Colorectal Neoplasms
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Humans
KW - Intercellular Signaling Peptides and Proteins
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait, Heritable
KW - Signal Transduction
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-79959851441&partnerID=MN8TOARS
U2 - 10.1371/journal.pgen.1002105
DO - 10.1371/journal.pgen.1002105
M3 - Article
C2 - 21655089
SN - 1553-7390
VL - 7
SP - e1002105
JO - PLoS Genetics
JF - PLoS Genetics
IS - 6
ER -