The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Jingyuan Xie(Shanghai Jiao Tong University), Lili Liu(Columbia University), Nikol Mladkova(Columbia University), Yifu Li(Columbia University), Hong Ren(Shanghai Jiao Tong University), Weiming Wang(Shanghai Jiao Tong University), Zhao Cui(Ministry of Education of the People's Republic of China), Li Lin(Shanghai Jiao Tong University), X. Hu(Shanghai Jiao Tong University), Xialian Yu(Shanghai Jiao Tong University), Jing Xu(Shanghai Jiao Tong University), Gang Liu(Ministry of Education of the People's Republic of China), Yaşar Çalışkan(Istanbul University), Carlo Sidore(Institute of Genetic and Biomedical Research), Olivia Balderes(Columbia University), Raphael J. Rosen(Columbia University), Monica Bodria(University of Parma), Francesca Zanoni(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Jun Y. Zhang(Columbia University), Priya Krithivasan(Columbia University), Karla Mehl(Columbia University), Maddalena Marasà(Columbia University), Atlas Khan(Columbia University), Fatih Ozay(Columbia University), Pietro A. Canetta(Columbia University), Andrew S. Bomback(Columbia University), Gerald B. Appel(Columbia University), Simone Sanna‐Cherchi(Columbia University), Matthew G. Sampson(Michigan Medicine), Laura Mariani(University of Michigan), Agnieszka Perkowska‐Ptasińska(Medical University of Warsaw), Magdalena Durlik(Medical University of Warsaw), Krzysztof Mucha(Medical University of Warsaw), Barbara Moszczuk(Medical University of Warsaw), Bartosz Foroncewicz(Medical University of Warsaw), Leszek Pączek(Medical University of Warsaw), Ireneusz Habura(University of Zielona Góra), Elisabet Ars(Universitat Autònoma de Barcelona), José Ballarín(Universitat Autònoma de Barcelona), Laila-Yasmin Mani(University of Bern), Bruno Vogt(University of Bern), Savaş Öztürk(Haseki Eğitim ve Araştırma Hastanesi), Abdülmecit Yıldız(Bursa Uludağ Üni̇versi̇tesi̇), Nurhan Seyahi(Istanbul University-Cerrahpaşa), Hakkı Arikan(Marmara University), Mehmet Koç(Marmara University), Taner Baştürk(Şişli Etfal Eğitim ve Araştırma Hastanesi), Gonca E. Karahan(Istanbul University), Sebahat Usta Akgül(Istanbul University), Mehmet Şükrü Sever(Istanbul University), Dan Zhang(Shanghai Jiao Tong University), Domenico Santoro(University of Messina), Mario Bonomini(University of Chieti-Pescara), Francesco Londrino(CTO Andrea Alesini), Loreto Gesualdo(University of Bari Aldo Moro), Jana Reiterová(Charles University), Vladimı́r Tesař(Charles University), Claudia Izzi(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), Silvana Savoldi, Donatella Spotti, Carmelita Marcantoni(Ospedale Cannizzaro), Piergiorgio Messa(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Marco Galliani(Ospedale Sandro Pertini), Dario Roccatello(Ospedale San Giovanni Bosco), Simona Granata(University of Verona), Gianluigi Zaza(University of Verona), Francesca Lugani(Istituto Giannina Gaslini), Gian Marco Ghiggeri(Istituto Giannina Gaslini), Isabella Pisani(University of Parma), Landino Allegri(University of Parma), Ben Sprangers(Rega Institute for Medical Research), Jin‐Ho Park(Seoul National University Hospital), Belong Cho(Seoul National University), Yon Su Kim(Seoul National University), Dong Ki Kim(Seoul National University), Hitoshi Suzuki(Juntendo University), Antonio Amoroso, Daniel Cattran(University of Toronto), Fernando C. Fervenza(Mayo Clinic), Antonello Pani(Azienda Ospedaliera G. Brotzu), Patrick Hamilton(Manchester University NHS Foundation Trust), Shelly Harris(Manchester University NHS Foundation Trust), Sanjana Gupta(University College London), Chris Cheshire(University College London), Stephanie Dufek(University College London), Naomi Issler(University College London), Ruth J. Pepper(University College London), John Connolly(University College London), Stephen H. Powis(University College London), Detlef Böckenhauer(University College London), Horia Stanescu(University College London), Neil Ashman(Royal London Hospital), Ruth J. F. Loos(Child Health and Development Institute), Eimear E. Kenny(Mount Sinai Health System), Matthias Wuttke(University of Freiburg), Kai‐Uwe Eckardt(Friedrich-Alexander-Universität Erlangen-Nürnberg), Anna Köttgen(University of Freiburg), Julia M. Hofstra(Radboud University Nijmegen), Marieke J. H. Coenen(Radboud University Nijmegen), Lambertus A. Kiemeney(Radboud University Nijmegen), Shreeram Akilesh(University of Washington), Matthias Kretzler(University of Michigan), Laurence H. Beck(Boston University), Bénédicte Stengel(Université Paris-Sud), Hanna Dêbiec(Sorbonne Université), Pierre Ronco(Sorbonne Université), Jack F.M. Wetzels(Radboud University Nijmegen), Magdalena Żołędziewska(Institute of Genetic and Biomedical Research), Francesco Cucca(Institute of Genetic and Biomedical Research), Iuliana Ionita‐Laza(Columbia University), Hajeong Lee(Seoul National University), Elion Hoxha(Universität Hamburg), Rolf A.K. Stahl(Universität Hamburg), Paul Brenchley(University of Manchester), Francesco Scolari(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), Ming‐Hui Zhao(Ministry of Education of the People's Republic of China), Ali G. Gharavi(Columbia University), Robert Kleta(The London College), Nan Chen(Shanghai Jiao Tong University), Krzysztof Kiryluk(Columbia University)
Cited by 218Open Access
Abstract
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.
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