Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach
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Qianqian Zhu1, Lori Shepherd1, Kathryn L. Lunetta2, Song Yao3, Qian Liu1, Qiang Hu1, Stephen A. Haddad4, Lara Sucheston-Campbell3, Jeannette T. Bensen5, Elisa V. Bandera6, Lynn Rosenberg4, Song Liu1, Christopher A. Haiman7, Andrew F. Olshan5, Julie R. Palmer4, Christine B. Ambrosone3
1Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
3Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
4Slone Epidemiology Center, Boston University, Boston, MA, USA
5Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
6Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
7Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
Qianqian Zhu, email: [email protected]
Keywords: causal variant, genome-wide association studies, fine-mapping
Received: April 28, 2016 Accepted: October 12, 2016 Published: November 04, 2016
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.
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