Abstract
BackgroundBreast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.MethodsWe performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.ResultsWe identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10− 8 - 6.0 × 10− 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70–0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78–0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91–0.97; p = 0.0017).ConclusionOur study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.
Highlights
Breast cancer is a partially heritable disease
Genome-wide association studies (GWAS) have identified over 180 common single nucleotide polymorphisms (SNPs) associated with risk of breast cancer [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. The majority of these SNPs were identified in European ancestry and East Asian ancestry populations, some unique SNPs have been identified in African American populations [21] and in Latina populations [22, 23]
Ranking SNPs by evidence for function For each of the top index SNPs we identified all of the other SNPs that they are in linkage disequilibrium (LD) with (R2 > 0.5) and that have a p value that is at within 2 log level of significance compared to the top SNP
Summary
Breast cancer is a partially heritable disease. Mutations in several high-penetrance genes including BRCA1 [1, 2], BRCA2 [3], and others [4] are associated with high risk of breast cancer among carriers and explain a fraction of the heritability. Genome-wide association studies (GWAS) have identified over 180 common single nucleotide polymorphisms (SNPs) associated with risk of breast cancer [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. The majority of these SNPs were identified in European ancestry and East Asian ancestry populations, some unique SNPs have been identified in African American populations [21] and in Latina populations [22, 23]. We report on fine mapping of the 6q25 locus in an expanded sample of Latinas
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