PROJECT SUMMARY The objective of our study is to identify ancestry related genetic variants contributing to differential risk of manifestations of both systemic lupus erythematosus (SLE) and multiple sclerosis (MS) in subjects of different genetic ancestries. SLE is an autoimmune disease with heterogenous features characterized by autoantibody formation and MS is an immune-mediated, demyelinating disorder. We will investigate the association between genetic ancestry and clinical outcomes of SLE and MS that are known to differ in prevalence and severity between SLE or MS patients of different races. Outcomes for SLE will include age of onset, autoantibody status, and lupus nephritis. Outcomes for MS will include age of onset, cognitive impairment, and MS severity score. We will study ~4,000 SLE and MS cases. In Aim 1, we will use ~2,000 SLE cases from the UCSF Lupus Genetics Study and California Lupus Epidemiology Study (CLUES) and ~2,000 MS cases from the Kaiser Permanente Northern California (KPNC) MS Research Program and Kaiser Permanente Southern California (KPSC) MS Sunshine Study to investigate the association of global ancestry and the outcomes of interest for SLE and MS. In Aim 2, we will investigate the association of local ancestry genome-wide and of candidate SLE and MS SNPs with the same clinical outcomes. In Aim 3, we will test for the association between both active and passive tobacco smoking and respective outcomes as well as test for gene-environment interaction between active and passive smoking and global and local ancestry. By establishing whether global and local genetic ancestry contribute to clinical heterogeneity and severity of SLE and MS, or if there are differences in gene-environment interaction with environmental exposures such as smoking, we might be able to target patients based on risk of disease outcomes by evaluating genetic ancestry of admixed patients. It might also be possible to predict disease manifestations and allow for early intervention and improved targeted treatment strategies limiting severity of disease and improving quality of life. This research project and associated training plan were developed in collaboration with my sponsor, Dr. Lisa Barcellos, co-sponsors, Drs. Lindsey Criswell and Laura Fejerman, and collaborators, Drs. Andres Cardenas and Priya Moorjani. The training plan emphasizes scientific productivity and building a strong knowledge of epidemiologic, biostatistical, and computational methods, as well as immunology and SLE and MS autoimmune disease processes. As a student at UC Berkeley, I am well supported by an institution that values rigorous scientific research and have access to many research and professional resources. Ultimately, the proposed research and achievement of the goals outlined in the training plan will allow me to become a multidisciplinary, independent investigator and facilitate my transition into a post-doctoral position and early-investigator faculty or research po...