Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

Abstract

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Figure 1. Results of the combined meta-analysis across all 20,612 individuals

Manhattan plot (a) and regional plots for genome-wide significant loci outside of the HLA region: (b) ITGAM-ITGAX locus, (c) CARD9 locus, (d) VAV3 locus, (e) DEFA locus (shaded area represents the region of common duplications involving DEFA1 and DEFA3 genes), (f) CFHR3,1-delta locus (shaded area represents the deletion of CFHR3 and CFHR1 genes), (g) HORMAD2 locus. X-axis represents physical distance in kb (hg-18 coordinates); Y-axis represents -log P values for association statistics.

Figure 2. Pleiotropic effects of IgAN GWAS loci and their cumulative effect on the age at disease onset

(a) A genetic susceptibility map was constructed based on all overlapping genome-wide significant loci reported in the NHGRI GWAS catalogue: diseases sharing a single locus with IgAN are indicated in yellow; diseases sharing multiple loci with IgAN are indicated in orange; solid arrows represent allelic associations that are identical to, or in tight LD (r2 > 0.5) with the IgAN risk alleles: concordant effects are indicated in red and opposed effects in blue; dotted arrows represent all other phenotype associations in the region. Of note, candidate gene or regional association studies were not included in this analysis. Inset: collapsed representation of pleiotropic relationships between IgAN and other phenotypes (only shared allelic effects are included with concordant effects indicated in red and opposed effects in blue). (b) Average age at diagnosis as a function of an individual’s risk allele burden (N=3,409 individuals with available data). (c) Average age at diagnosis by quintile of genetic risk (error bars represent 95% confidence interval for the mean). Abbreviations: IgAD: IgA Deficiency; RA: Rheumatoid Arthritis; PBC: Primary Biliary Cirrhosis; MN: Membranous Nephropathy; OA: Osteoarthritis; HCC: Hepatocellular Carcinoma; SLE: Systemic Lupus Erythematosus; UC: Ulcerative Colitis; CD: Crohn’s Disease; T1D: Type I Diabetes; AMD: Age-related Macular Degeneration.

Figure 3. Autoimmunity/inflammatory loci and risk of IgAN

(a) A quantile-quantile plot of IgAN associations for 582 unique non-HLA SNPs previously associated with autoimmune or immune-mediated diseases at p < 5 × 10⁻⁸ in the NHGRI GWAS catalogue. When tested for association with IgAN, an unexpectedly large number of SNPs deviate from the null expectation (empiric p < 1 × 10⁻⁴, Supplementary Figure 9). (b) The KEGG enrichment map for the genes residing within autoimmunity loci associated with IgAN at p < 0.05 (q < 0.25). The size of nodes reflects −log10-transformed P-values of the adjusted hypergeometric enrichment test in GSEA. The edges represent pathway similarity as defined by an overlap coefficient. The top overrepresented KEGG pathway is the “Intestinal Immune Network for IgA Production” (gene set overlap coefficient = 25%, enrichment p < 1.0 × 10⁻¹⁶). Individual genes intersecting top-ranked KEGG pathways are provided in Supplementary Figure 10c.

Figure 4. IgAN genetic risk is correlated with worldwide pathogen diversity

(a) Correlation between IgAN genetic risk score (X-axis) and the level of local pathogen diversity (Y-axis) among the HGDP populations (linear regression line and its 95% confidence intervals, Pearson’s correlation coefficient = 0.62, P = 6 × 10⁻⁷); (b) Stepwise feature selection among all pathogen subgroups confirmed helminth diversity as the single best predictor of IgAN genetic risk (Pearson’s correlation coefficient = 0.68, P = 1 × 10⁻⁸); (c) Weaker correlation was also evident for bacterial diversity (top panel, Pearson’s correlation coefficient = 0.56, P = 1 × 10⁻⁵), but not for protozoan or viral diversity (middle and bottom panels). The pathogen diversity metrics were scaled and standardized across all populations; error bars represent 95% confidence interval for the mean; for detailed analysis refer to Supplementary Table 22.