Multiple myeloma (MM) is a malignancy consisting of a neoplastic clone of plasma cells, the terminally-differentiated B lymphocytes responsible for antibody production. It is the second most common cause of death among the hematological malignancies. Despite recent advances in treatment, the 5-year survival rate remains under 40%. African Americans experience incidence rates over 2-fold higher than those of Whites; the reasons for the racial differences in disease rates are unknown. Risk is also 2- to 3-fold elevated among persons with a family history of multiple myeloma and/or its precursor, monoclonal gammopathy of undetermined significance (MGUS). We hypothesize that there is a genetic component to multiple myeloma risk and that part of the excess risk in African Americans is mediated through inherited variation. In this application, we propose to perform a genome-wide association study to identify common genetic variants that contribute to multiple myeloma risk in the African American population. More specifically, we will examine 1,000,000 genetic markers in 2,072 African American multiple myeloma cases and 4,645 African American controls. Cases for this study will be recruited and specimens collected by means of a network of collaborations with NCI/SEER population-based cancer registries (California, Detroit, Louisiana and New Jersey) and clinical centers in 6 regions with large African-American populations (University of Alabama at Birmingham, Johns Hopkins University, Emory University, Karmanos Cancer Institute/Wayne State University, Northwestern University, University of Chicago, and M.D. Anderson Cancer Center/University of Texas). Controls will consist of 4,645 healthy unaffected African-American subjects from across the U.S. We will assess the generalizabilty of our findings by association testing of the top 100 SNPs in 1,500 MM cases and 3,710 controls of European origin in multiple existing studies from the U.S. and Australia. In addition, with NCI consultant Dr. Landgren, we will examine the associations of the risk variants with the precursor, MGUS among 700 African-American subjects with MGUS and 1,400 controls recruited from NHANES. In this proposal we will utilize the strengths of collaborative, large-scale genetic research to identify common risk alleles for MM in a population (African American) that experiences a health disparity with respect to this cancer. In addition to illuminating etiology of multiple myeloma in African Americans, we hope to discover new pathways that can be exploited for drug development. Our ultimate goal is to reduce the health disparity experienced by African Americans due to this fatal cancer.