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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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. Genome-wide association studies (GWAS) have identified several colorectal cancer (CRC) susceptibility polymorphisms near genes that encode proteins in the bone morphogenetic protein (BMP) pathway. However, most of the inherited susceptibility to CRC remains unexplained. We investigated three of the best candidate BMP genes (GREM1, BMP4, and BMP2) for additional polymorphisms associated with CRC. By extensive validation of polymorphisms with only modest evidence of association in the initial phases of the GWAS, we identified new, independent CRC predisposition polymorphisms close to BMP4 (rs1957636) and BMP2 (rs4813802). Near GREM1, we used additional genotyping around the GWAS-identified polymorphism rs4779584 to demonstrate two independent signals represented by rs16969681 and rs11632715. Common genes with modest effects on disease risk are becoming harder to identify, and approaches based on informed candidate gene selection may become increasingly attractive. In addition, genetic fine mapping around polymorphisms identified in GWAS can deconvolute associations which have arisen owing to two independent functional variants. These types of study can identify some of the apparently missing heritability of common disease.

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