The rapid evolution of array techniques and the completion of the map of the human genome have led to a host of genomewide association studies over the past few years. Yet many of these studies have been disappointing; they identify genes that confer only a moderate increase in risk and explain only a small fraction of the known hereditary characteristics of the diseases. 1 However, the results of genomewide association studies for idiopathic membranous nephropathy conducted by Stanescu and coworkers, reported in this issue of the Journal, are more striking than usual. 2 The authors report highly significant associations between membranous nephropathy and single-nucleotide polymorphisms (SNPs) in genes that encode HLA-DQA1 and the M-type phospholipase A2 receptor (PLA2R).

The relative risks for the two implicated alleles are remarkably similar in three independent French, Dutch, and British cohorts; for the HLADQA1 SNP (rs2187668), the odds ratios were calculated as 4.48, 3.76, and 5.33, respectively, and the corresponding odds ratios for the receptor SNP (rs4664308) were 1.87, 2.27, and 2.10. Even more striking is the multiplicative increase in the odds ratio for each risk allele added. Among persons carrying one risk allele at the rs4664308 locus, the odds ratio increases from 2.22 to 8.49 with the addition of one risk allele and to 31.03 with the addition of two risk alleles at the rs2187668 locus. Furthermore, the odds ratio for persons who are doubly homozygous is 78.46. Even though membranous nephropathy is rare, such an increase in risk has substantial implications on the individual level. The annual incidence of membranous nephropathy is approximately 1 case per 100,000 population—representing a lifelong risk of about 1 per 1000 for a person in a Western country who reaches average life expectancy. This implies a lifelong increased risk for persons with this specific genotype—at a level where screening and preventive measures would be meaningful, if effective interventions become available. The results reported by Stanescu et al. confirm the findings of two recent studies from Asia (Taiwan and Korea) that used a candidate gene ap-