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

Krzysztof Kiryluk, Yifu Li, Francesco Scolari, Simone Sanna-Cherchi, Murim Choi, Miguel Verbitsky, David Fasel, Sneh Lata, Sindhuri Prakash, Samantha Shapiro, Clara Fischman, Holly J. Snyder, Gerald Appel, Claudia Izzi, Battista Fabio Viola, Nadia Dallera, Lucia Del Vecchio, Cristina Barlassina, Erika Salvi, Francesca Eleonora BertinettoAntonio Amoroso, Silvana Savoldi, Marcella Rocchietti, Alessandro Amore, Licia Peruzzi, Rosanna Coppo, Maurizio Salvadori, Pietro Ravani, Riccardo Magistroni, Gian Marco Ghiggeri, Gianluca Caridi, Monica Bodria, Francesca Lugani, Landino Allegri, Marco Delsante, Mariarosa Maiorana, Andrea Magnano, Giovanni Frasca, Emanuela Boer, Giuliano Boscutti, Claudio Ponticelli, Renzo Mignani, Carmelita Marcantoni, Domenico Di Landro, Domenico Santoro, Antonello Pani, Rosaria Polci, Sandro Feriozzi, Silvana Chicca, Marco Galliani, Maddalena Gigante, Loreto Gesualdo, Pasquale Zamboli, Giovanni Giorgio Battaglia, Maurizio Garozzo, Dita Maixnerová, Vladimir Tesar, Frank Eitner, Thomas Rauen, Jürgen Floege, Tibor Kovacs, Judit Nagy, Krzysztof Mucha, Leszek Pazek, Marcin Zaniew, Maa'Gorzata Mizerska-Wasiak, Maria Roszkowska-Blaim, Krzysztof Pawlaczyk, Daniel Gale, Jonathan Barratt, Lise Thibaudin, Francois Berthoux, Guillaume Canaud, Anne Boland, Marie Metzger, Ulf Panzer, Hitoshi Suzuki, Shin Goto, Ichiei Narita, Yasar Caliskan, Jingyuan Xie, Ping Hou, Nan Chen, Hong Zhang, Robert J. Wyatt, Jan Novak, Bruce A. Julian, John Feehally, Benedicte Stengel, Daniele Cusi, Richard P. Lifton, Ali G. Gharavi

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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.

Original languageEnglish
Pages (from-to)1187-1196
Number of pages10
JournalNature genetics
Volume46
Issue number11
DOIs
Publication statusPublished - Nov 5 2014

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ASJC Scopus subject areas

  • Genetics

Cite this

Kiryluk, K., Li, Y., Scolari, F., Sanna-Cherchi, S., Choi, M., Verbitsky, M., Fasel, D., Lata, S., Prakash, S., Shapiro, S., Fischman, C., Snyder, H. J., Appel, G., Izzi, C., Viola, B. F., Dallera, N., Del Vecchio, L., Barlassina, C., Salvi, E., ... Gharavi, A. G. (2014). Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nature genetics, 46(11), 1187-1196. https://doi.org/10.1038/ng.3118