Commentary on Kopp JB, Smith MW, Nelson GW, et al: MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175-1184, 2008 and Kao WH, Klag MJ, Meoni LA, et al: MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet40:1185-1192, 2008.
hronic kidney disease (CKD) is a complex genetic disorder. Familial aggregation of both diabetic and nondiabetic kidney disease is known1-3 and traits such as glomerular ﬁltration rate and albuminuria are highly heritable.4-7 Aggregation of CKD by race adds a further dimension to its genetic basis, suggesting gene ﬂow from separate ancestral gene pools. The markedly exaggeratedrisk of CKD in the African American population of the United States has been appreciated for several decades. In 2006, the US Renal Data System documented rates of treated kidney failure (end-stage renal disease [ESRD]) that were 3.6-fold greater in African Americans than whites.8 Although African Americans have the highest rates of hypertension and the second highest rates of diabetes prevalenceamong ethnic groups in the United States,9,10 increased prevalence of these primary diseases is insufﬁcient to explain the excess risk of CKD.11,12 While socioeconomic status, lifestyle factors, and clinical factors such as hypertension and diabetes could contribute to as much as 40% of the excess risk,13 African Americans still carry a nearly 2-fold greater risk of CKD relative to the whitepopulation.13,14 The increased risk extends to kidney disease of several etiologies including diabetic nephropathy,15 hypertensive kidney disease,16 lupus nephritis,17 focal segmental sclerosis (FSGS),18 HIV-associated nephropathy (HIVAN),19 and glomerulonephritis.20 It encompasses both an increased susceptibility to CKD,16 as well as a more rapid progression to ESRD.21 Both quantitative linkageapproaches and genetic association studies have been applied to identify disease genes for CKD with limited success.22 Association studies provide a powerful strategy to uncover multiple genes with smaller effects. However a serious weakness is the propensity to false-positive results from genetic differences related to population substructure or admixture, especially if the prevalence of disease alsodiffers in the component popula-
tions. Self-reported race may be associated with cryptic population stratiﬁcation, making replication of study results in conﬁrmatory investigations more challenging.23 The gene pool of African Americans residing in the United States reﬂects the mixing of the native Africans, mainly from Western Africa, with European and Native American peoples, and has about10% to 20% European admixture.24 Minority populations have often been underrepresented in genetic association studies. Two independent studies in the October 2008 issue of Nature Genetics25,26 successfully exploit the genetic architecture of population admixture in African Americans, using an analytic strategy called “mapping by admixture linkage disequilibrium” or MALD27-29 to detect a geneconferring increased risk for FSGS and for ESRD in nondiabetic individuals. To understand the ﬁndings in these manuscripts, 2 important concepts need to be explained. The ﬁrst is admixture, which refers to the formation of a new population by interbreeding between individuals from genetically divergent parental populations. The second is linkage disequilibrium (LD), which describes the co-occurrenceof 2 alleles at different loci on the same chromosome more often than would be predicted by random chance and is a measure of cosegregation of alleles in a population. MALD is especially appropriate to the study of diseases that differ in frequency between ethnic groups and requires recent admixture, measurable differences in the frequency of disease-causing alleles between parental populations,...