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. 2013 Dec 15;22(24):5048-55.
doi: 10.1093/hmg/ddt337. Epub 2013 Jul 12.

Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans

Hansong Wang  1 , Christopher A Haiman, Terrilea Burnett, Barbara K Fortini, Laurence N Kolonel, Brian E Henderson, Lisa B Signorello, William J Blot, Temitope O Keku, Sonja I Berndt, Polly A Newcomb, Mala Pande, Christopher I Amos, Dee W West, Graham Casey, Robert S Sandler, Robert Haile, Daniel O Stram, Loïc Le Marchand
Affiliations

Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans

Hansong Wang et al. Hum Mol Genet. .

Abstract

Genome-wide association studies of colorectal cancer (CRC) in Europeans and Asians have identified 21 risk susceptibility regions [29 index single-nucleotide polymorphisms (SNPs)]. Characterizing these risk regions in diverse racial groups with different linkage disequilibrium (LD) structure can help localize causal variants. We examined associations between CRC and all 29 index SNPs in 6597 African Americans (1894 cases and 4703 controls). Nine SNPs in eight regions (5q31.1, 6q26-q27, 8q23.3, 8q24.21, 11q13.4, 15q13.3, 18q21.1 and 20p12.3) formally replicated in our data with one-sided P-values <0.05 and the same risk directions as reported previously. We performed fine-mapping of the 21 risk regions (including 250 kb on both sides of the index SNPs) using genotyped and imputed markers at the density of the 1000 Genomes Project to search for additional or more predictive risk markers. Among the SNPs correlated with the index variants, two markers, rs12759486 (or rs7547751, a putative functional variant in perfect LD with it) in 1q41 and rs7252505 in 19q13.1, were more strongly and statistically significantly associated with CRC (P < 0.0006). The average per allele risk was improved using the replicated index variants and the two new markers (odds ratio = 1.14, P = 6.5 × 10(-16)) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 × 10(-10)). The contribution of the two new risk SNPs to CRC heritability was estimated to be 1.5% in African Americans. This study highlights the importance of fine-mapping in diverse populations.

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Figures

Figure 1.
Figure 1.
Allele frequencies in published reports (blue for Europeans and yellow for East Asians) and in African Americans (red). SNPs replicated in African Americans are marked with an asterisk.
Figure 2.
Figure 2.
P-value plot for the 1q41 risk locus. The SNP with the smallest P-value in African Americans, rs12759486, is shown as a purple diamond. r2 is in relation to this SNP in EUR from the 1000 Genomes Project. Grey circles are SNPs with no r2 estimation due to low MAF or because the SNP is not in older versions of the 1000 Genomes data. The plot was generated using LocusZoom (16).
Figure 3.
Figure 3.
P-value plot for the 19q13 risk locus. The SNP with the smallest P-value in African Americans, rs7252505, is shown as a purple diamond. r2 is in relation to this SNP in EUR from the 1000 Genomes Project. Grey circles are SNPs with no r2 estimation due to low MAF or because the SNP is not in older versions of the 1000 Genomes data. The plot was generated using LocusZoom.
See this image and copyright information in PMC

References

    1. Broderick P., Carvajal-Carmona L., Pittman A.M., Webb E., Howarth K., Rowan A., Lubbe S., Spain S., Sullivan K., Fielding S., et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat. Genet. 2007;39:1315–1317. doi:10.1038/ng.2007.18. - DOI - PubMed
    1. Cui R., Okada Y., Jang S.G., Ku J.L., Park J.G., Kamatani Y., Hosono N., Tsunoda T., Kumar V., Tanikawa C., et al. Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. Gut. 2011;60:799–805. doi:10.1136/gut.2010.215947. - DOI - PMC - PubMed
    1. Dunlop M.G., Dobbins S.E., Farrington S.M., Jones A.M., Palles C., Whiffin N., Tenesa A., Spain S., Broderick P., Ooi L.-Y., et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat. Genet. 2012;44:770–776. doi:10.1038/ng.2293. - DOI - PMC - PubMed
    1. Houlston R.S., Cheadle J., Dobbins S.E., Tenesa A., Jones A.M., Howarth K., Spain S.L., Broderick P., Domingo E., Farrington S., et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat. Genet. 2010;42:973–977. doi:10.1038/ng.670. - DOI - PMC - PubMed
    1. Houlston R.S., Webb E., Broderick P., Pittman A.M., Di Bernardo M.C., Lubbe S., Chandler I., Vijayakrishnan J., Sullivan K., Penegar S., et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat. Genet. 2008;40:1426–1435. doi:10.1038/ng.262. - DOI - PMC - PubMed

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