A genome-wide admixture scan identifies MYH 9 as a candidate locus associated with non-diabetic end stage renal disease in African Americans

End stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans. This led to the hypothesis that susceptibility alleles for ESRD have a higher frequency in West African than European gene pool. We performed a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and demonstrated a highly significant association between excess African ancestry and non-diabetic ESRD (LOD 5.70) but not diabetic ESRD (LOD 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% credible interval 0.39 – 0.63) compared to African ancestry. Multiple common SNPs (allele frequency ranging from 0.2 to 0.6) in the gene that encodes non-muscle myosin heavy chain type II isoform A (MYH9) were associated with 2-4 times greater risk of non-diabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans. End stage renal disease (ESRD) is the near-total loss of kidney function requiring treatment of 472,000 patients with dialysis or transplantation in the US1. Diabetes and hypertension are the two leading reported causes of treated ESRD in the U.S. accounting for 44% and 27% of incident cases respectively1. African Americans have consistently had a much higher rate of ESRD than European Americans in the US. In 2005, African-Americans had a 3.7 times higher age adjusted risk of ESRD. The risk ratio by assigned primary cause of ESRD was 3.8 for hypertension, 2.6 for diabetes, 2.3 for glomerulonephritis, 2.1 for the other causes of kidney disease1. While lower socioeconomic status and poorer access to health care explains some of this excess risk2-4, African Americans appear to have greater risk than European Americans after these factors are taken into account. Family studies show clustering of ESRD independent of hypertension and diabetes5, 6 with one large study shows stronger aggregation in African Americans6. Studies attempting to detect susceptibility genes for ESRD and other complex diseases are challenging due to the late age of onset, causing difficulty in collecting multiply-affected families, and because linkage analysis has suggested that there are no genes of high penetrance (>4-fold increased risk) in populations of European descent, the focus of most published studies7, 8. For these reasons, ESRD is an excellent phenotype for whole genome association analysis, an approach with enhanced power to detect common variants of modest penetrance, and with the further advantage that unrelated individuals can be studied. We performed a scan for ESRD genes using a particular type of whole genome association analysis, termed admixture mapping or mapping by admixture linkage disequilibrium (MALD) Linda Kao et al. Page 2 Nat Genet. Author manuscript; available in PMC 2009 April 1. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript 9-11. Admixture mapping is particularly suitable for finding genetic risk alleles that differ in frequency between populations which we hypothesized might be the case for ESRD. The basic principle of admixture mapping relies on the small proportion of genetic variants that differ in frequency across populations of different ancestries12. When mixing occurs between genetically heterogeneous populations, the resulting admixed population inherits chromosomal regions of either one ancestry or the other, and these regions can be identified by genotyping markers that exhibit substantially different allele frequencies between ancestral populations. Admixture mapping methodology is feasible as a result of the development of a map of admixture mapping markers in African Americans13 and appropriate analytical methods14, 15. Moreover, the admixture mapping methodology has been validated as a promising way of finding susceptibility loci for common complex conditions, such as prostate cancer16 and multiple sclerosis17. The central hypothesis of this study is that some ESRD susceptibility alleles are present at higher frequency in African than in European Americans. Thus, the identification of ESRD susceptibility alleles is possible by screening the genome in African Americans with ESRD, searching for regions of the genome where individuals with the disease have more (or less) African ancestry than their genome-wide average. Not only do previous studies provide evidence for a genetic basis to kidney disease and ESRD7, 18, it has been hypothesized that there may exist a common set of susceptibility genes for progression to ESRD irrespective of the inciting cause, e.g. diabetic or non-diabetic19. A secondary goal of our study was to test the hypothesis that the genetic variants that confer a higher risk for ESRD in African Americans are relevant to a broad range of ESRD phenotypes.