MYH9 is associated with nondiabetic end-stage renal disease in African Americans

Abstract

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 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% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.

Figure 1

(a) LOD score from genome-wide scan for diabetic (gray) and non-diabetic (black) ESRD. The genome-wide score for non-diabetic ESRD was 5.70 and 0.47 for diabetic ESRD. The highest locus-specific LOD for diabetic ESRD was 2.79 on chromosome 11 and 8.56 on chromosome 22 for non-diabetic ESRD. (b) Difference between estimated European ancestry at different loci of the genome and the genome-wide average for 669 non-diabetic ESRD (black) and 806 controls (gray). The estimated European ancestry on chromosome 22 was lower than the average across the entire genome among non-diabetic ESRD cases but not controls.

Figure 2

Region of association with non-diabetic ESRD on chromosome 22. The peak LOD score was 9.31, and the 95% credible interval spanned from 31.388650 to 35.039798 Mb, covering 22 genes.

Figure 3

Effect of MYH9 SNPs on the association between local ancestry in the region of chromosome 22q12 and non-diabetic ESRD. The results of the local ancestry estimates were obtained from 14 different ANCESTRYMAP runs, each containing one of the 14 SNPs at a time. The light gray bars indicate the highly significant associations between local ancestry at the locus of interest on chromosome 22q12 and case-control status. The dark gray bars show the greatly reduced associations between local ancestry and case-control status after the inclusion of MYH9 SNP in the logistic regression model. Three SNPs (rs4821480, rs2032487, and rs4821481), in particular, accounted for almost the entire significance of the association between local ancestry and case-control status. The LD pattern of 14 SNPs in MYH9 shown is that of the African-American FIND and CHOICE participants. In addition, known rare mutations Mendelian conditions are shown for the region of MYH9 containing the 14 SNPs studied.