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.

Figure 1. Fine mapping around the known CRC risk SNP close to GREM1 (15q13.3).

Results for meta-analysis of UK2 and Scotland2 are shown. Both significance of association (−log₁₀(P)) and effect size (β) are presented. The original CRC-associated tagSNPs are shown in blue. The SNP with the clearly strongest association signal is the genotyped SNP rs16969681.

Figure 2. Search for additional colorectal cancer susceptibility SNPs near GREM1, BMP4, and BMP2.

Association signals from discovery phase around GREM1, BMP4 and BMP2 are shown. For GREM1, the labelled SNPs are highyl correlated tagSNPs originally reported as associated with CRC; these signals are non-independent. For BMP4 and BMP2, the labelled SNPs are the original tagSNPs and the subsequently proven new signals at rs1957636 and rs4813802 respectively.