Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy
Adam P. Levine, Melanie Chan, Omid Sadeghi‐Alavijeh, Edwin Wong, H. Terence Cook, Sofie Ashford, Keren Carss, Martin Christian, Matthew Hall, Claire L. Harris, Paul McAlinden, Kevin J. Marchbank, Stephen D. Marks, Heather Maxwell, Karyn Mégy, Christopher J. Penkett, Monika Mozere, Kathleen Stirrups, Salih Tuna, Julie Wessels, Deborah Whitehorn, MPGN/DDD/C3 Glomerulopathy Rare Disease Group, NIHR BioResource, Sally A. Johnson, Daniel P. Gale
Abstract
Significance Statement A minority of cases of primary membranoproliferative GN are familial, caused by mutations in complement genes, and nonfamilial cases have also been reported to harbor such mutations. To characterize the genetic factors contributing to this disease, the authors analyzed whole-genome data from 165 cases of primary membranoproliferative GN and 10,250 control individuals, including 146 cases and 6442 controls who were unrelated and of European ancestry. Although they observed no significant enrichment of rare variants in complement genes or exome-wide among cases compared with controls, they found that the HLA locus was strongly associated with primary membranoproliferative GN, a finding replicated in an independent cohort. These findings imply that in most cases, primary membranoproliferative GN is driven by autoimmunity rather than an underlying monogenic disorder of complement regulation. Background Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. Methods We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource–Rare Diseases Study. We examined copy number, rare, and common variants. Results Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) ( P =3.29×10 −8 ; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 ( P =1.21×10 −8 ; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. Conclusions We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.