title: Genetic risk variants for membranous nephropathy: extension of and association with other chronic kidney disease aetiologies.
abstract: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Previous genome-wide association studies (GWAS) of 300 000 genotyped variants identified MN-associated loci at HLA-DQA1 and PLA2R1.
  
  
  
  We used a combined approach of genotype imputation, GWAS, human leucocyte antigen (HLA) imputation and extension to other aetiologies of chronic kidney disease (CKD) to investigate genetic MN risk variants more comprehensively. GWAS using 9 million high-quality imputed genotypes and classical HLA alleles were conducted for 323 MN European-ancestry cases and 345 controls. Additionally, 4960 patients with different CKD aetiologies in the German Chronic Kidney Disease (GCKD) study were genotyped for risk variants at HLA-DQA1 and PLA2R1.
  
  
  
  In GWAS, lead variants in known loci [rs9272729, HLA-DQA1, odds ratio (OR) = 7.3 per risk allele, P = 5.9 × 10-27and rs17830558, PLA2R1, OR = 2.2, P = 1.9 × 10-8] were significantly associated with MN. No novel signals emerged in GWAS of X-chromosomal variants or in sex-specific analyses. Classical HLA alleles (DRB1*0301-DQA1*0501-DQB1*0201 haplotype) were associated with MN but provided little additional information beyond rs9272729. Associations were replicated in 137 GCKD patients with MN (HLA-DQA1: P = 6.4 × 10-24; PLA2R1: P = 5.0 × 10-4). MN risk increased steeply for patients with high-risk genotype combinations (OR > 79). While genetic variation in PLA2R1 exclusively associated with MN across 19 CKD aetiologies, the HLA-DQA1 risk allele was also associated with lupus nephritis (P = 2.8 × 10-6), type 1 diabetic nephropathy (P = 6.9 × 10-5) and focal segmental glomerulosclerosis (P = 5.1 × 10-5), but not with immunoglobulin A nephropathy.
  
  
  
  PLA2R1 and HLA-DQA1 are the predominant risk loci for MN detected by GWAS. While HLA-DQA1 risk variants show an association with other CKD aetiologies, PLA2R1 variants are specific to MN.
authors.affiliation: Department of Internal Medicine IV, Medical Center-University of Freiburg, Freiburg, Germany.|Center for Medical Biometry and Medical Informatics, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Sekula
authors.affiliation: Department of Internal Medicine IV, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.affiliation: Department of Internal Medicine IV, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wuttke
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.affiliation: Department of Internal Medicine IV, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Powis
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Brenchley
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.affiliation: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Department of Internal Medicine IV, Medical Center-University of Freiburg, Freiburg, Germany.|Center for Medical Biometry and Medical Informatics, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
keywords: chronic kidney disease; genome-wide association study; membranous nephropathy