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, Xiaofan Hu, Xialian Yu, Gang Liu, Yasar Caliskan, Carlo Sidore, Olivia Balderes, Raphael J Rosen, Monica Bodria, Francesca Zanoni, Priya Krithivasan, Karla Mehl, Maddalena Marasa, Atlas KhanFatih 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, Patrick Hamilton, Robert Kleta, Paul Brenchley

Research output: Contribution to journalArticlepeer-review


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
Pages (from-to)1600
JournalNature Communications
Issue number1
Publication statusPublished - 30 Mar 2020


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