Breast cancer, the most frequently diagnosed cancer among women, is the second leading cause of cancer death. Current breast cancer mortality rates in the United States, including Tennessee and South Carolina are considerably higher among African Americans than among Caucasians. Little is understood about the etiology of breast cancer nor do we know what factors might explain why African American women tend to be diagnosed with more aggressive disease than Caucasian women. Recent genome-wide association studies (GWAS) have opened opportunities to investigate breast cancer etiology. Approximately 20 susceptibility loci have been identified from the GWAS conducted among women of Chinese and European ancestry. Recent reports found breast cancer risk consistently increased among Caucasian and Chinese women with an increasing number of some of these loci. During the three years of this proposed project we anticipate an additional 15 to 20 susceptibility loci for breast cancer will be identified through GWAS, including our study conducted among Asian women. The relevance of these loci to African American women remains under-investigated, and data from our recent pilot investigation have showed that the majority of the initially-reported genetic risk variants identified in Caucasian and Chinese cannot be directly replicated among African Americans. The purpose of this proposed project is to investigate approximately 21 GWAS-identified loci to discover genetic risk variants relevant for African American women. In addition, we will establish a breast cancer risk assessment model that incorporates clinical and genetic factors to better identify high-risk African American women since the only existing breast cancer risk assessment model for African Americans does not include genetic markers. This full project will be supported by the Cancer Outreach Core.