Abstract
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10−8, odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10−8; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10-8; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
Highlights
Twin studies indicate that heritable factors account for 35% of the variation in risk of developing colorectal cancer (CRC)[1]
Genome-wide association studies (GWAS) conducted primarily in European[4,5,6,7,8,9,10,11,12] and Asian[13,14,15,16] populations have vindicated the long-held belief that part of the heritable risk of CRC is attributable to common, low-risk variants
These GWAS have provided insights into the biological basis of CRC, highlighting the role of genes within the bone morphogenetic protein signalling pathway (BMP2, BMP4, GREM1 and SMAD7) 4,11 and some candidate genes (e.g. CDH1/CDH3), as well as genes not previously implicated in CRC (e.g. POLD3, TERC, CDKN1A and SHROOM2) 8,10
Summary
Twin studies indicate that heritable factors account for 35% of the variation in risk of developing colorectal cancer (CRC)[1]. Genome-wide association studies (GWAS) conducted primarily in European[4,5,6,7,8,9,10,11,12] and Asian[13,14,15,16] populations have vindicated the long-held belief that part of the heritable risk of CRC is attributable to common, low-risk variants. These GWAS have provided insights into the biological basis of CRC, highlighting the role of genes within the bone morphogenetic protein signalling pathway (BMP2, BMP4, GREM1 and SMAD7) 4,11 and some candidate genes (e.g. CDH1/CDH3), as well as genes not previously implicated in CRC (e.g. POLD3, TERC, CDKN1A and SHROOM2) 8,10. Imputation of untyped variants in GWAS data using publicly available reference datasets increases the number of variants that can be tested for an association with CRC risk
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