The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Jingyuan Xie, Lili Liu, Nikol Mladkova, Yifu Li, Hong Ren, Weiming Wang, Zhao Cui, Li Lin, Xiaofan Hu, Xialian Yu, Jing Xu, Gang Liu, Yasar Caliskan, Carlo Sidore, Olivia Balderes, Raphael J. Rosen, Monica Bodria, Francesca Zanoni, Jun Y. Zhang, Priya KrithivasanKarla Mehl, Maddalena Marasa, Atlas Khan, Fatih Ozay, Pietro A. Canetta, Andrew S. Bomback, Gerald B. Appel, Simone Sanna-Cherchi, Matthew G. Sampson, Laura H. Mariani, Agnieszka Perkowska-Ptasinska, Magdalena Durlik, Krzysztof Mucha, Barbara Moszczuk, Bartosz Foroncewicz, Leszek Pączek, Ireneusz Habura, Elisabet Ars, Jose Ballarin, Laila Yasmin Mani, Bruno Vogt, Savas Ozturk, Abdülmecit Yildiz, Nurhan Seyahi, Hakki Arikan, Mehmet Koc, Taner Basturk, Gonca Karahan, Sebahat Usta Akgul, Mehmet Sukru Sever, Dan Zhang, Domenico Santoro, Mario Bonomini, Francesco Londrino, Loreto Gesualdo, Jana Reiterova, Vladimir Tesar, Claudia Izzi, Silvana Savoldi, Donatella Spotti, Carmelita Marcantoni, Piergiorgio Messa, Marco Galliani, Dario Roccatello, Simona Granata, Gianluigi Zaza, Francesca Lugani, Gian Marco Ghiggeri, Isabella Pisani, Landino Allegri, Ben Sprangers, Jin Ho Park, Be Long Cho, Yon Su Kim, Dong Ki Kim, Hitoshi Suzuki, Antonio Amoroso, Daniel C. Cattran, Fernando C. Fervenza, Antonello Pani, Patrick Hamilton, Shelly Harris, Sanjana Gupta, Chris Cheshire, Stephanie Dufek, Naomi Issler, Ruth J. Pepper, John Connolly, Stephen Powis, Detlef Bockenhauer, Horia C. Stanescu, Neil Ashman, Ruth J.F. Loos, Eimear E. Kenny, Matthias Wuttke, Kai Uwe Eckardt, Anna Köttgen, Julia M. Hofstra, Marieke J.H. Coenen, Lambertus A. Kiemeney, Shreeram Akilesh, Matthias Kretzler, Lawrence H. Beck, Benedicte Stengel, Hanna Debiec, Pierre Ronco, Jack F.M. Wetzels, Magdalena Zoledziewska, Francesco Cucca, Iuliana Ionita-Laza, Hajeong Lee, Elion Hoxha, Rolf A.K. Stahl, Paul Brenchley, Francesco Scolari, Ming hui Zhao, Ali G. Gharavi, Robert Kleta, Nan Chen, Krzysztof Kiryluk

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Original languageEnglish (US)
Article number1600
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xie, J., Liu, L., Mladkova, N., Li, Y., Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X., Xu, J., Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R. J., Bodria, M., Zanoni, F., Zhang, J. Y., ... Kiryluk, K. (2020). The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. Nature communications, 11(1), [1600]. https://doi.org/10.1038/s41467-020-15383-w