Journal
PLOS GENETICS
Volume 7, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002105
Keywords
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Categories
Funding
- Oxford Comprehensive Biomedical Research Centre
- EU
- Wellcome Trust Centre for Human Genetics, Oxford [075491/Z/04]
- Medical Research Council [G0000657-53203]
- CORE
- Scottish Executive Chief Scientist's Office [K/OP/2/2/D333, CZB/4/449]
- National Cancer Institute, National Institutes of Health [CA-95-011]
- Australian Colorectal Cancer Family Registry [UO1 CA097735]
- USC Familial Colorectal Neoplasia Collaborative Group [UO1 CA074799]
- Mayo Clinic Cooperative Family Registry for Colon Cancer Studies [UO1 CA074800]
- Ontario Registry for Studies of Familial Colorectal Cancer [UO1 CA074783]
- Seattle Colorectal Cancer Family Registry [UO1 CA074794]
- University of Hawaii Colorectal Cancer Family Registry [UO1 CA074806]
- Cancer Research UK Fellowship [C31250/A10107]
- UK Medical Research Council
- Cancer Research Wales, Tenovus & Wales Gene Park
- Cancer Research UK [12076] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124] Funding Source: researchfish
- Chief Scientist Office [CZB/4/449] Funding Source: researchfish
- Medical Research Council [MC_PC_U127527198, G0301096, MC_U127527198] Funding Source: researchfish
- Tenovus Cancer Care [PhD2009/L27] Funding Source: researchfish
- MRC [MC_U127527198, MC_PC_U127527198, G0301096] Funding Source: UKRI
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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 = 3.93x10(-10)) and BMP2 (rs4813802, P = 4.65x10(-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 = 5.33x10(-8)) and rs11632715 (P = 2.30x10(-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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