Abstract
Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.
Highlights
Genome-wide association studies (GWAS) premised on the “common disease, common variants” hypothesis have made great strides in identifying common genetic variants associated with a variety of phenotypes [1]
We evaluated the performance of the preferential linkage disequilibrium (LD) approach in an African American (AA) population, following up breast cancer genome-wide association studies (GWAS) hits
We investigated the associations of 74 breast cancer risk variants previously discovered by GWAS in 8,315 AA women from the AMBER consortium
Summary
Genome-wide association studies (GWAS) premised on the “common disease, common variants” hypothesis have made great strides in identifying common genetic variants associated with a variety of phenotypes [1]. The association signal attenuates as the linkage disequilibrium (LD) between the causal variant(s) and the GWAS-discovered variant decreases, when the causal variant(s) are rare in the population. The majority of GWAS have focused on populations of European descent, where the causal variants can be far from the associated marker due to strong LD, making it difficult to localize the causal variants [5, 6]. Studies in populations with lower average LD often yield shorter distances between causal variants and the associated marker, helping to narrow down the causal variants underlying the disease associations [5, 14]
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