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