Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.
Krzysztof KirylukYifu LiFrancesco ScolariSimone Sanna-CherchiMurim ChoiMiguel VerbitskyDavid FaselSneh LataSindhuri PrakashSamantha ShapiroClara FischmanHolly J SnyderGerald AppelClaudia IzziBattista Fabio ViolaNadia DalleraLucia Del VecchioCristina BarlassinaErika SalviFrancesca Eleonora BertinettoAntonio AmorosoSilvana SavoldiMarcella RocchiettiAlessandro AmoreLicia PeruzziRosanna CoppoMaurizio SalvadoriPietro RavaniRiccardo MagistroniGian Marco GhiggeriGianluca CaridiMonica BodriaFrancesca LuganiLandino AllegriMarco DelsanteMariarosa MaioranaAndrea MagnanoGiovanni FrascaEmanuela BoerGiuliano BoscuttiClaudio PonticelliRenzo MignaniCarmelita MarcantoniDomenico Di LandroDomenico SantoroAntonello PaniRosaria PolciSandro FeriozziSilvana ChiccaMarco GallianiMaddalena GiganteLoreto GesualdoPasquale ZamboliGiovanni Giorgio BattagliaMaurizio GarozzoDita MaixnerováVladimir TesarFrank EitnerThomas RauenJürgen FloegeTibor KovacsJudit NagyKrzysztof MuchaLeszek PączekMarcin ZaniewMałgorzata Mizerska-WasiakMaria Roszkowska-BlaimKrzysztof PawlaczykDaniel P GaleJonathan BarrattLise ThibaudinFrancois BerthouxGuillaume CanaudAnne BolandMarie MetzgerUlf PanzerHitoshi SuzukiShin GotoIchiei NaritaYasar CaliskanJingyuan XiePing HouNan ChenHong ZhangRobert J WyattJan NovakBruce A JulianJohn FeehallyBenedicte StengelDaniele CusiRichard P LiftonAli G GharaviPublished in: Nature genetics (2014)
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.