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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.

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