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

Nature communications 2020

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

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: DRB11501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA10501 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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