Replication Study Results and Combined Meta-Analysis.

<p>Combined association results for 12 SNPs representing 5 independent regions that reached genome-wide significance in the original GWAS. The combined effect estimates (per allele odds ratios) in the replication cohorts were all direction-consistent with the ones in the original GWAS cohorts. Significant heterogeneity was noted only for the second HLA locus represented by rs9357155 and rs2071543.</p><p>Q-test: P-value for the Cochrane's Q statistic for heterogeneity, NS: heterogeneity test not significant,</p>*<p>heterogeneity P<0.05,</p>**<p>heterogeneity P<0.01;</p><p>I²: Heterogeneity Index (0–100%), where <25% corresponds to low, 50%–75% to medium, and >75% to high level of heterogeneity;</p><p>OR: Additive (per-allele) Odds Ratio;</p>#<p>Han and Eskin random effects model.</p

Genetic risk and IgAN–attributable ESRD among major US ethnicities.

<p>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.</p

Worldwide geospatial risk analysis.

<p>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).</p

Differences in the distribution of the 7-SNP genetic risk score by ethnicity.

<p>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 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002765#pgen.1002765.s001" target="_blank">Figure S1</a>.</p

The best predictive model for IgAN based on all the genotyped SNPs and their pairwise interaction terms.

<p>This model represents the solution of a stepwise logistic regression algorithm (BIC-based stepwise model selection). The coefficients from this model are used to refine the risk score for IgAN.</p

Multiplicative interaction between Chr. 22q12 (rs2412971) and Chr. 1q32 (rs6677604) loci.

<p>The allelic effects of rs2412971-A by genotype class of rs9275596 (top signal in the HLA, no interaction) and rs6677604 (top signal in at <i>CFHR1/R3</i> 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 <i>CFHR3/R1</i>. 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.</p

Conditional analysis of the <i>HLA-DQB1, HLA-DQA1, HLA-DRB1</i> locus.

<p>Conditional analysis of the <i>HLA-DQB1, HLA-DQA1, HLA-DRB1</i> locus.</p

Correlation of average country latitude with country-specific genetic risk and IgAN–attributable ESRD across the European continent.

<p>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.</p

Haplotype analysis of rs9275224, rs2856717, rs9275424, and rs9275596 at the HLA-DQB1/DRB1 locus.

<p>The most common haplotype of 4 major alleles (GCAT) is used as a reference to derive odds ratios for all other haplotypes. Only common haplotypes (frequency >1%) are tested for association.</p

The comparison of the original and the newly refined IgAN risk score.

<p>The expanded version of this table can be found in supplemental material (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002765#pgen.1002765.s010" target="_blank">Table S7</a>).</p>#<p>Number of analyzed individuals with 100% non-missing genotypes across all 7 scored loci.</p>*<p>2: Nagelkerke R square (expressed as percentage).</p>**<p>C-statistic: area under the ROC curve.</p>***<p>Odds ratio per one standard deviation of the standardized risk score.</p>****<p>Wald's test for risk score as a quantitative predictor of disease status.</p