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Meta-Analysis
. 2012;8(6):e1002765.
doi: 10.1371/journal.pgen.1002765. Epub 2012 Jun 21.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis

Affiliations
Meta-Analysis

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis

Krzysztof Kiryluk et al. PLoS Genet. 2012.

Abstract

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹⁰), with heterogeneity detected only at the PSMB9/TAP1 locus (I² = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻⁴). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²⁸). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Multiplicative interaction between Chr. 22q12 (rs2412971) and Chr. 1q32 (rs6677604) loci.
The allelic effects of rs2412971-A by genotype class of rs9275596 (top signal in the HLA, no interaction) and rs6677604 (top signal in at CFHR1/R3 locus on Chr. 1q32, significant interaction). The protective effect of rs2412971-A allele is reversed in homozygotes for the rs6677604-A allele, which tags a deletion in CFHR3/R1. The allelic effects are expressed on the log-odds scale and correspond to beta coefficients of the logistic regression model. Error bars correspond to 95% confidence intervals.
Figure 2
Figure 2. Differences in the distribution of the 7-SNP genetic risk score by ethnicity.
Only healthy control participants of the replication studies that were fully genotyped at all 7 loci were used in this analysis. Similar to the GWAS study, the risk score distributions were significantly different by ethnicity (ANOVA p = 2.1×10−38). The corresponding differences in the distribution of risk alleles are depicted in Figure S1.
Figure 3
Figure 3. Worldwide geospatial risk analysis.
Surface interpolation of the standardized risk score over Africa and Euroasia (main), and Americas (inset). Symbols represent the locations of sampled populations: HGDP (circles), HapMap-III (diamonds), and healthy controls from this study (triangles).
Figure 4
Figure 4. Correlation of average country latitude with country-specific genetic risk and IgAN–attributable ESRD across the European continent.
The South to North latitude is indicated on the X-axis. The median genetic risk (x) is indicated on the right Y-axis. The following incidence and prevalence metrics (o) are indicated on the left Y-axis: (panel a) the incidence of ESRD due to IgAN per million population (correlation with latitude: r = 0.54, p = 0.05); (panel b) the prevalence of ESRD due to IgAN per million population (correlation with latitude: r = 0.47, p = 0.10); (panel c) the percent of IgAN patients among all ESRD cases (correlation with latitude: r = 0.67, p = 0.01); and (panel d) among ESRD cases due to primary glomerular disease (correlation with latitude: r = 0.71, p = 0.006). All p-values are derived based on a two-sided hypothesis test.
Figure 5
Figure 5. High-resolution geospatial risk analysis for Italy.
A well defined region of higher genetic risk was uncovered in Northern Italy that centers on Valtrompia, Brescia, and Cremona (median standardized risk scores 0.31, 0.24 and 0.24, respectively). The healthy individuals from Valtrompia had the highest risk scores when compared to 16 other Italian populations sampled.
Figure 6
Figure 6. Genetic risk and IgAN–attributable ESRD among major US ethnicities.
The relationship between IgAN risk scores (red line) and IgAN incidence and prevalence (bars) among US ethnicities are shown. The following metrics of IgAN occurrence are depicted: (panel a) the incidence of ESRD due to IgAN per million population by ethnicity, (panel b) the prevalence of ESRD due to IgAN per million population by ethnicity, (panel c) percent of IgAN among the total ESRD population by ethnicity; and (panel d) percent of IgAN among ESRD due to glomerular disease by ethnicity.

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