MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

Abstract

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 x 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.

Figure 1

Genome-wide admixture analysis and chromosome 22 gene localization. (a) Lod scores of the case-control statistic (blue) and the locus-genome score (green) across the genome from the ANCESTRYMAP analysis. (The case control statistic was converted to a lod score as described in Methods.) The x axis shows a concatenated set of chromosomes (gray) with locations of the MALD markers interrogated indicated below (black). (b) Lod scores for alternate runs of the ANCESTRYMAP analysis, and the 95% credible interval for the location of a genetic factor responsible for the chromosome 22 MALD peak spans from 34,422,950 to 35,655,902 bp (build 36). The locus-genome statistic, with the 95% credible interval shaded, is shown along with the percent African ancestry in cases and controls.

Figure 2

MYH9 linkage disequilibrium and associations. Shown (black, below r2 plot) is the 3′ two-thirds of MYH9, comprising exons 2 through 41. The top is a modified Haploview r2 plot for the known 120 SNPs that are polymorphic in YRI. Below in blue are the two known recombination hot spots (blue horizontal bars); SNPs defining and localizing the most highly associated haplotype region, E, along with their susceptible alleles are shown in red. The genomic order of the SNPs is rs7078, rs12107, rs735853, rs5756129, rs5756130, rs11549907, rs875725, rs2187776, rs4821480, rs2032487, rs4821481, rs3752462, rs5756152, rs1557539, rs1005570, rs16996674 and rs16996677. The table shows allele frequencies for African American idiopathic and HIV + FSGS, hypertensive and diabetic (type 2) ESKD, and idiopathic European American FSGS along with controls for each group. Frequencies in boldface were still significant after correction for multiple testing (see Methods) for the dominant or recessive analyses; underlined frequencies are for associations nominally significant (P < 0.05) and supporting (in the same direction as) the African American FSGS associations (Table 4).

Figure 3

Frequencies of the three genotypes for the MYH9 SNPs rs4821480, rs2032487, rs4821481 and rs3752462, and haplotype E-1, the most frequent haplotype containing the four SNPs, in African American and European American FSGS cases and controls. Odds ratios and P values for the recessive model comparing FSGS cases and controls are shown.