Membranous nephropathy (MN) is the leading cause of primary nephrotic syndrome in white adults and a major cause of nephrotic syndrome across global populations. In MN, circulating antibodies permeate the glomerular basement membrane and, in the subepithelial space, form immune complexes with antigens on podocyte membranes. Recently, the M-type phospholipase A 2 receptor (PLA 2 R) was identified as the specific podocyte antigen responsible for eliciting immune complex formation with circulating antibodies. Anti-PLA 2 R antibodies are detected in 60%-75% of idiopathic MN cases across many ethnicities. 1,2 Additional podocyte autoantigens-mitochondrial SOD 2, aldose reductase, a-enolase, and neutral endopeptidase 3,4 -have likewise emerged as potential targets of MN-specific autoantibodies, potentially filling in the missing gaps in PLA 2 R antibody-negative disease. These breakthroughs have established MN as a disease of autoantibodies and, in many ways, challenge the continued use of the term idiopathic MN. 5 Nonetheless, we still do not know why, exactly, such autoantibodies develop in MN. The identified podocyte antigens are endogenously expressed; only the autoantibodies against such antigens are detected in patients with MN.Previous case reports of familial forms of MN have suggested a genetic predisposition to disease. 6 In a recent genomewide association study (GWAS) in three European populations (French, Dutch, and British), Stanescu et al. described associations of MN with the HLA locus on chromosome 6p21 and the PLA2R1 locus (encoding PLA 2 R) on chromosome 2q24. 7 The association with HLA was significant in all three patient samples, whereas the association with PLA2R1 was significant in the Dutch and British samples (as well as in joint analysis of all three populations). Strikingly, whereas the risk of disease was relatively modest in individuals with risk alleles at any one locus, the odds ratio for MN was an astronomical 78.5 (95% confidence interval [95% CI], 34.6 to 178.2) in individuals homozygous for risk alleles at both loci, indicative of strong genetic interaction. This GWAS was thus unusual because the effect sizes imparted by the combined risk alleles were very large, suggesting a potential role for genetics for noninvasive screening or risk stratification of MN. This study also provided an independent line of evidence implicating PLA2R1 in the pathogenesis of disease, suggesting that sequence variants within PLA2R1 may alter expression or function of PLA 2 R, potentially unmasking it as an autoantigen that, in conjunction with the right MHC haplotype, results in activation of T cells and stimulation of autoantibody production. Limitations of this GWAS included the relatively small sample size, which precluded precise localization of the risk alleles within each locus. Particularly, the origin of the signal within the MHC locus remained unclear, 8 because this region has a very complicated structure, and class I and class II response loci may each contain multiple independent haplotypes wi...