The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 × 10 −23 , n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.The prevalence of chronic kidney disease (CKD) in the United States is currently estimated at 13% and is associated with significant morbidity and mortality 1 . Approximately 100,000 Americans develop end-stage kidney (renal) disease (ESKD) each year. The cumulative lifetime risk for ESKD varies by ancestry, and is approximately 7.5% for African Americans and 2.1% for European Americans2. African Americans have a disproportionate risk for several forms of CKD, among them diabetic nephropathy3, hypertensive nephrosclerosis4, lupus nephritis5, focal segmental glomerulosclerosis (FSGS) 6 and HIV-associated nephropathy (a distinct form of FSGS, also termed collap-sing glomerulopathy)7 , 8. The disproportionate risk for CKD may be partially explained by differences in social-economic status, lifestyle factors and clinical factors such as blood pressure control, but most of the increased risk remains unexplained9.FSGS is a clinical syndrome involving podocyte injury and glomerular scarring, and includes genetic forms with autosomal dominant or recessive mendelian inheritance, reactive forms associated with other illnesses (including HIV-1 disease) or medications, and a sporadic, idiopathic form, which accounts for the majority of cases 10 . Recent data suggest an increase in the incidence of FSGS, which currently accounts for up to 3% of ESKD cases6. African Americans have a fourfold increased risk for sporadic FSGS11 and an 18-to 50-fold increased risk for HIV-1-associated FSGS7 ,12 . Individuals of African descent also have increased risk for FSGS in other geographic regions, further suggesting that genetic factors contribute to these disparities 11 .A strategy for identifying genes underlying such ancestry-driven health disparities is mapping by admixture linkage disequilibrium (MALD). MALD has successfully identified a genomic region associated with prostate cancer 13 subsequently replicated by a genome-wide association study14, as well as genes associated with hypertension15, multiple scl...