Oncotarget 83160 www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget/ Oncotarget, 2016, Vol. 7, (No. 50), pp: 83160-83176 Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach Qianqian Zhu 1 , Lori Shepherd 1 , Kathryn L. Lunetta 2 , Song Yao 3 , Qian Liu 1 , Qiang Hu 1 , Stephen A. Haddad 4 , Lara Sucheston-Campbell 3 , Jeannette T. Bensen 5 , Elisa V. Bandera 6 , Lynn Rosenberg 4 , Song Liu 1 , Christopher A. Haiman 7 , Andrew F. Olshan 5 , Julie R. Palmer 4 , Christine B. Ambrosone 3 1 Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA 2 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA 3 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Slone Epidemiology Center, Boston University, Boston, MA, USA 5 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 6 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA 7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA Correspondence to: Qianqian Zhu, email: qianqian.zhu@roswellpark.org Keywords: causal variant, genome-wide association studies, fne-mapping Received: April 28, 2016 Accepted: October 12, 2016 Published: November 04, 2016 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 identifcation of bona fde causal variants. We previously developed the preferential LD approach, a novel method that successfully identifed 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 identifed 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 signifcance level α=0.05, suggesting race-specifcity of the identifed 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 identifed 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 identifed 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. INTRODUCTION 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]. Typically, the GWAS-identifed variants for any particular phenotype cumulatively explain only a small portion of the phenotypic variation [2]. One explanation for the so-called missing heritability problem is that the variants identifed Research Paper