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 novel 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 geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the 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.
Highlights
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 performed principal component analyses to assure adequate ancestry matching between cases and controls (Supplementary Figure 1)
We previously demonstrated that the worldwide distribution of IgAN risk alleles was correlated with distance from Africa and paralleled the prevalence of IgAN2,3
Summary
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. The two largest studies, both based on Asian discovery cohorts, detected four additional non-HLA loci, including chromosome 1q32, comprising a common deletion of the complement factor H related CFHR3 and CFHR1 genes (CFHR3,1-delta); 8p23 comprising the α-defensin (DEFA) gene cluster; 17p13 (including TNFSF13), and 22q12 (including HORMAD2 and several other genes)[3,4]. These GWAS loci explain about 5% of the total disease risk. To identify new disease loci, we performed a GWAS twice the size of the prior largest study and have analyzed a discovery cohort based predominantly on European subjects
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