The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
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 
Published: March 2020

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.