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

Nat Genet. 2014 Nov;46(11):1187-96. doi: 10.1038/ng.3118. Epub 2014 Oct 12.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • CARD Signaling Adaptor Proteins / genetics*
  • CD11b Antigen / genetics*
  • Genetic Loci / genetics*
  • Genetic Pleiotropy / genetics
  • Genome-Wide Association Study
  • Glomerulonephritis, IGA / genetics*
  • HLA-D Antigens / genetics*
  • Host-Pathogen Interactions / genetics
  • Humans
  • Immunity / genetics*
  • Intestines / immunology
  • Intestines / parasitology
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins c-vav / genetics*


  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • CD11b Antigen
  • HLA-D Antigens
  • ITGAM protein, human
  • Proto-Oncogene Proteins c-vav
  • VAV3 protein, human

Associated data

  • dbGaP/PHS000431.V1.P1
  • dbGaP/PHS000431.V2.P1