Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas

Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Human Molecular Genetics (Impact Factor: 6.39). 01/2012; 21(8):1907-17. DOI: 10.1093/hmg/ddr617
Source: PubMed


Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.

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    • "Panels for these analyses involving Mexican Americans have been developed by Collins-Schramm et al. (2004; 100 AIMs) and Tian et al. (2007; 5,287 AIMs), and similar panels have been developed for Hispanic/Latino populations in general by Price et al. (2007; 1,649 AIMs) and Mao et al. (2007; 2,120 AIMs). Examples of the specificity of this approach include: (a) Price et al. (2007), who estimated that in Latinos and Mexicans from Los Angeles, where Native American ancestry is close to 50%, admixture mapping should be 15% to 30% more powerful per sample than in Colombians or Brazilians, who have lower percentages of this ancestry; and (b) Fejerman et al. (2012), who identified a region in chromosome 6 related to breast cancer susceptibility in Latinas. A detailed review of the studies in this area, however, is outside the scope of the present work. "
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