Genome-wide association study identifies susceptibility loci for IgA nephropathy

Abstract

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10⁻²⁶ and 4.84 × 10⁻⁹ and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

Figure 1. Manhattan plot of p-values for SNP associations to IgAN

Plot of the observed p-values versus chromosomal location; highlighted are the ten independent loci followed up in additional cohorts. The dashed line corresponds to the follow-up threshold.

Figure 2. High resolution view of the MHC locus

The X-axis represents physical distance (kb). The left Y-axis represent the −log(p-values) for the association statistics. The −log(p-values) in the discovery and combined cohorts are shown as blue circles and red diamonds, respectively. The right Y-axis represents the average recombination rates based on the phased HapMap haplotypes. The recombination rates are shown by the light blue line (a) The three intervals associated with IgA nephropathy reside within a 0.54 Mb segment on chromosome 6. The shaded areas correspond to regional plots in lower panels; (b) Regional plot for the interval containing HLA-DQB1, DQA1, and DRB1. The classical HLA alleles imputed in the discovery cohort (green triangles) formed a protective haplotype DQB1*0602-DQA1*0102-DRB1*1501. (c) Regional plot for the second MHC interval: SNPs typed in the combined cohorts reside within the PSMB8 gene. (d) Regional plot for the HLA-DPB2, DPB1, and DPA1 interval. The lower panels for (b–d) represent LD heatmaps (D') calculated based on the actual genotype data of the Beijing cohort.

Figure 3. Analysis of the Chr. 1 and Chr 22. loci

(a) Regional association plot of the chromosome 1q32 locus; while the most strongly associated SNP resides within the CFH gene, it is a perfect proxy for CFHR1,3Δ. The lower panel represents the LD heatmap (D') calculated based on the genotype data of the Beijing cohort. (b) Haplotype analysis revealed five common haplotypes (H-1 to H-5) in the Beijing discovery cohort (freq. > 0.01). The haplotype frequencies, corresponding tag-SNPs and reported disease associations are shown^–,,,,. The H2 haplotype perfectly tags CFHR1,3Δ. The odds ratios (ORs) and 95% confidence intervals (95% CIs) are calculated in reference to H-1, which has an identical frequency among cases and controls. *** p=7.7 × 10⁻⁶ for comparison of H-2 versus all other haplotypes. (c) Regional association plot of the chromosome 22 locus: the strongest association stems from the SNPs residing within HORMAD2, but the area of association spans over ~ 0.7 Mb region containing multiple genes.

Figure 4. Differences in the distributions of protective alleles by ethnicity

(a) Distributions of protective alleles by ethnicity and case-control status. Numbers of protective alleles were scored for the combined Asian (N=3,556) and European (N=2,410) cohorts. Europeans harbor much greater numbers of protective alleles. The differences in the distribution of protective alleles between Asians and Europeans are highly significant within both case and control groups (Chi-square p=4.9 × 10⁻⁷² and p=6.4 × 10⁻⁶⁰ for cases and controls, respectively). (b) Distributions of protective alleles among the three HapMap populations: there were highly significant differences between Asian (CHB+JPT) vs. Europeans (CEU, p=1.3×10⁻³) and Asian vs. Yorubans (YRI, p=7.1×10⁻⁶) populations.