The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.
Jingyuan XieLili LiuNikol MladkovaYifu LiHong RenWeiming WangZhao CuiLi LinXiaofan HuXialian YuJing XuGang LiuYasar CaliskanCarlo SidoreOlivia BalderesRaphael J RosenMonica BodriaFrancesca ZanoniJunying ZhangPriya KrithivasanKarla MehlMaddalena MarasàAtlas KhanFatih OzayPietro A CanettaAndrew S BombackGerald B AppelSimone Sanna-CherchiMatthew G SampsonLaura H MarianiAgnieszka Perkowska-PtasinskaMagdalena DurlikKrzysztof MuchaBarbara MoszczukBartosz ForoncewiczLeszek PączekIreneusz HaburaElisabet ArsJose BallarinLaila-Yasmin ManiBruno VogtSavas OzturkAbdülmecit YildizNurhan SeyahiHakki ArikanMehmet KocTaner BasturkGonca KarahanSebahat Usta AkgulMehmet Sukru SeverDan ZhangDomenico SantoroMario BonominiFrancesco LondrinoLoreto GesualdoJana ReiterovaVladimir TesarClaudia IzziSilvana SavoldiDonatella SpottiCarmelita MarcantoniPiergiorgio MessaMarco GallianiDario RoccatelloSimona GranataGianluigi ZazaFrancesca LuganiGianMarco GhiggeriIsabella PisaniLandino AllegriBen SprangersJin Ho ParkBeLong ChoYon Su KimDong Ki KimHitoshi SuzukiAntonio AmorosoDaniel C CattranFernando C FervenzaAntonello PaniPatrick HamiltonShelly HarrisSanjana GuptaChris CheshireStephanie Dufek-KamperisNaomi IsslerRuth J PepperJohn ConnollyStephen PowisDetlef BockenhauerHoria C StanescuNeil AshmanRuth J F LoosEimear E KennyMatthias WuttkeKai-Uwe EckardtAnna KottgenJulia M HofstraMarieke J H CoenenLambertus A KiemeneyShreeram AkileshMatthias KretzlerLawrence H BeckBenedicte StengelHanna DebiecPierre RoncoJack F M WetzelsMagdalena ZoledziewskaFrancesco CuccaIuliana Ionita-LazaHajeong LeeElion HoxhaRolf A K StahlPaul BrenchleyFrancesco ScolariMing-Hui ZhaoAli G GharaviRobert KletaNan ChenKrzysztof KirylukPublished in: Nature communications (2020)
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.