A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses

A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis

BACKGROUND: Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome-wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population. RESULTS: A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10(-8)), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10(-11)). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235). CONCLUSIONS: Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses

A Colorectal Cancer Susceptibility New Variant at 4q26 in the Spanish Population Identified by Genome-Wide Association Analysis

<div><p>Background</p><p>Non-hereditary colorectal cancer (CRC) is a complex disorder resulting from the combination of genetic and non-genetic factors. Genome–wide association studies (GWAS) are useful for identifying such genetic susceptibility factors. However, the single loci so far associated with CRC only represent a fraction of the genetic risk for CRC development in the general population. Therefore, many other genetic risk variants alone and in combination must still remain to be discovered. The aim of this work was to search for genetic risk factors for CRC, by performing single-locus and two-locus GWAS in the Spanish population.</p><p>Results</p><p>A total of 801 controls and 500 CRC cases were included in the discovery GWAS dataset. 77 single nucleotide polymorphisms (SNP)s from single-locus and 243 SNPs from two-locus association analyses were selected for replication in 423 additional CRC cases and 1382 controls. In the meta-analysis, one SNP, rs3987 at 4q26, reached GWAS significant p-value (p = 4.02×10⁻⁸), and one SNP pair, rs1100508 CG and rs8111948 AA, showed a trend for two-locus association (p = 4.35×10⁻¹¹). Additionally, our GWAS confirmed the previously reported association with CRC of five SNPs located at 3q36.2 (rs10936599), 8q24 (rs10505477), 8q24.21(rs6983267), 11q13.4 (rs3824999) and 14q22.2 (rs4444235).</p><p>Conclusions</p><p>Our GWAS for CRC patients from Spain confirmed some previously reported associations for CRC and yielded a novel candidate risk SNP, located at 4q26. Epistasis analyses also yielded several novel candidate susceptibility pairs that need to be validated in independent analyses.</p></div

Best SNP×SNP interactions validated in the phase II and meta-analysis results.

<p>SNP: Single Nucleotide Polymorphism; OR: HFCC Odds Ratio; P: value associated with HFCC OR (1 df).</p>†<p>The nearest gene or the gene where the SNP is located.</p

Top results in the global meta-analysis.

<p>CHR: Chromosome; BP: Base pair position; SNP: Single Nucleotide Polymorphism; A1: Reference allele (minor allele); p: Fixed-effects p-value; p(R): Random-effects p-value; OR: Fixed-effects Odds Ratio; OR(R): Random-effects Odds Ratio; Q: p-value for heterogeneity of OR; I: effect size for heterogeneity of OR.</p><p>*SNPs selected by two-locus association analyses in the NXC-GWAS sample.</p>†<p>The nearest gene or the gene where the SNP is located.</p>‡<p>According to UCSC genome browser (NCBI36/hg18) and dbSNP build 130.</p

Meta-analysis of SNPs validated in the phase II.

<p>CHR: Chromosome; SNP: Single Nucleotide Polymorphism; BP: Base pair position; A1: Reference allele (minor allele); P: Fixed-effects p-value; P(R): Random-effects p-value; OR: Fixed-effects Odds Ratio; OR(R): Random-effects Odds Ratio; Q: p-value for heterogeneity of OR; I: effect size for heterogeneity of OR.</p><p>*SNPs selected by two-locus association analyses in the NXC-GWAS sample.</p>†<p>The nearest gene or the gene where the SNP is located.</p>‡<p>According to UCSC genome browser (NCBI36/hg18) and dbSNP build 130.</p

Results of previously reported SNPs that were successfully genotyped or imputed in our analysis.

<p>CHR: Chromosome; SNP: Single Nucleotide Polymorphism. The last four columns show the allele reported frequency in cases (F A), in controls (F U) and, the p and the Odds Ratio (OR) values obtained in the NXC-GWAS sample.</p><p>In bold type, SNPs with a nominal p-value below 0.05.</p>†<p>The nearest gene or the gene where the SNP is located.</p><p>*SNPs genotyped (not imputed).</p

Manhattan plot of CRC-GWAS.

<p>Blue and red horizontal lines correspond to p values of 6.97×10⁻⁴ and 5×10⁻⁸ respectively.</p

SNPs validated in the phase II.

<p>CHR: Chromosome; SNP: Single Nucleotide Polymorphism; BP: Base pair position; A1: Reference allele (minor allele). The last eight columns show the minor allele frequency in cases (MAF A), the minor allele frecuency in controls (MAF U) and, the p and the Odds Ratio (OR) values obtained in each analyzed sample.</p><p>*SNPs selected by two-locus association analyses in the NXC-GWAS sample.</p>†<p>The nearest gene or the gene where the SNP is located.</p>‡<p>According to UCSC genome browser (NCBI36/hg18) and dbSNP build 130.</p