The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Jingyuan Xie
,
Lili Liu
,
Nikol Mladkova
,
Yifu Li
,
Hong Ren
(1)
,
Weiming Wang
(2)
,
Zhao Cui
(3, 4)
,
Li Lin
(5)
,
Xiaofan Hu
,
Xialian Yu
,
Jing Xu
(6)
,
Gang Liu
(7)
,
Yasar Caliskan
,
Carlo Sidore
(8, 9, 10)
,
Olivia Balderes
,
Raphael Rosen
,
Monica Bodria
(11)
,
Francesca Zanoni
,
Jun Zhang
(12)
,
Priya Krithivasan
,
Karla Mehl
,
Maddalena Marasa
,
Atlas Khan
,
Fatih Ozay
,
Pietro Canetta
,
Andrew Bomback
,
Gerald Appel
,
Simone Sanna-Cherchi
,
Matthew Sampson
,
Laura Mariani
,
Agnieszka Perkowska-Ptasinska
,
Magdalena Durlik
,
Krzysztof Mucha
,
Barbara Moszczuk
,
Bartosz Foroncewicz
,
Leszek Pączek
,
Ireneusz Habura
,
Elisabet Ars
,
Jose Ballarin
,
Laila-Yasmin Mani
,
Bruno Vogt
,
Savas Ozturk
,
Abdülmecit Yildiz
,
Nurhan Seyahi
,
Hakki Arikan
,
Mehmet Koc
,
Taner Basturk
,
Gonca Karahan
,
Sebahat Usta Akgul
,
Mehmet Sukru Sever
,
Dan Zhang
,
Domenico Santoro
,
Mario Bonomini
,
Francesco Londrino
,
Loreto Gesualdo
,
Jana Reiterova
,
Vladimir Tesar
,
Claudia Izzi
,
Silvana Savoldi
,
Donatella Spotti
,
Carmelita Marcantoni
,
Piergiorgio Messa
,
Marco Galliani
,
Dario Roccatello
,
Simona Granata
,
Gianluigi Zaza
,
Francesca Lugani
,
Gianmarco Ghiggeri
,
Isabella Pisani
,
Landino Allegri
,
Ben Sprangers
,
Jin-Ho Park
,
Belong Cho
,
Yon Su Kim
,
Dong Ki Kim
,
Hitoshi Suzuki
,
Antonio Amoroso
,
Daniel Cattran
,
Fernando Fervenza
,
Antonello Pani
,
Patrick Hamilton
,
Shelly Harris
,
Sanjana Gupta
,
Chris Cheshire
,
Stephanie Dufek
,
Naomi Issler
,
Ruth Pepper
,
John Connolly
,
Stephen Powis
,
Detlef Bockenhauer
,
Horia Stanescu
,
Neil Ashman
,
Ruth Loos
,
Eimear Kenny
,
Matthias Wuttke
,
Kai-Uwe Eckardt
,
Anna Köttgen
,
Julia Hofstra
,
Marieke Coenen
,
Lambertus Kiemeney
,
Shreeram Akilesh
,
Matthias Kretzler
,
Lawrence Beck
,
Benedicte Stengel
,
Hanna Debiec
,
Pierre Ronco
,
Jack Wetzels
,
Magdalena Zoledziewska
,
Francesco Cucca
,
Iuliana Ionita-Laza
,
Hajeong Lee
,
Elion Hoxha
,
Rolf Stahl
,
Paul Brenchley
,
Francesco Scolari
,
Ming-Hui Zhao
,
Ali Gharavi
,
Robert Kleta
,
Nan Chen
,
Krzysztof Kiryluk
1
QMUL -
Queen Mary University of London
2 NANJING INSTITUTE OF GEOLOGY AND PALAEONTOLOGY - Nanjing Institute of Geology and Palaeontology
3 Peking University [Beijing]
4 Renal Division [Beijing, China]
5 NIGPAS-CAS - Nanjing Institute of Geology and Palaeontology
6 SDAU - Shandong Agricultural University
7 State Key Lab. of Information Engineering in Surveying, Mapping and Remote Sensing
8 Michigan State University [East Lansing]
9 Istituto di Virologia Vegetale
10 UNISS - Università degli Studi di Sassari = University of Sassari [Sassari]
11 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
12 Xjtu - Xi'an Jiaotong University
2 NANJING INSTITUTE OF GEOLOGY AND PALAEONTOLOGY - Nanjing Institute of Geology and Palaeontology
3 Peking University [Beijing]
4 Renal Division [Beijing, China]
5 NIGPAS-CAS - Nanjing Institute of Geology and Palaeontology
6 SDAU - Shandong Agricultural University
7 State Key Lab. of Information Engineering in Surveying, Mapping and Remote Sensing
8 Michigan State University [East Lansing]
9 Istituto di Virologia Vegetale
10 UNISS - Università degli Studi di Sassari = University of Sassari [Sassari]
11 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
12 Xjtu - Xi'an Jiaotong University
Jingyuan Xie
- Function : Author
Lili Liu
- Function : Author
- PersonId : 1210104
- ORCID : 0000-0002-2622-9669
Nikol Mladkova
- Function : Author
Yifu Li
- Function : Author
Xiaofan Hu
- Function : Author
Xialian Yu
- Function : Author
Yasar Caliskan
- Function : Author
Olivia Balderes
- Function : Author
Raphael Rosen
- Function : Author
Francesca Zanoni
- Function : Author
Jun Zhang
- Function : Author
- PersonId : 1210105
- ORCID : 0000-0003-4996-8699
Priya Krithivasan
- Function : Author
Karla Mehl
- Function : Author
Maddalena Marasa
- Function : Author
- PersonId : 1210106
- ORCID : 0000-0003-0712-2329
Atlas Khan
- Function : Author
Fatih Ozay
- Function : Author
- PersonId : 1210107
- ORCID : 0000-0002-1383-7892
Pietro Canetta
- Function : Author
- PersonId : 1210108
- ORCID : 0000-0003-1130-5486
Andrew Bomback
- Function : Author
- PersonId : 1210109
- ORCID : 0000-0001-5449-1667
Gerald Appel
- Function : Author
Simone Sanna-Cherchi
- Function : Author
- PersonId : 1210110
- ORCID : 0000-0002-6185-948X
Matthew Sampson
- Function : Author
Laura Mariani
- Function : Author
Agnieszka Perkowska-Ptasinska
- Function : Author
Magdalena Durlik
- Function : Author
Krzysztof Mucha
- Function : Author
- PersonId : 1210111
- ORCID : 0000-0002-6613-7638
Barbara Moszczuk
- Function : Author
Bartosz Foroncewicz
- Function : Author
Leszek Pączek
- Function : Author
Ireneusz Habura
- Function : Author
Elisabet Ars
- Function : Author
Jose Ballarin
- Function : Author
Laila-Yasmin Mani
- Function : Author
Bruno Vogt
- Function : Author
- PersonId : 802464
- ORCID : 0000-0002-1548-6387
Savas Ozturk
- Function : Author
Abdülmecit Yildiz
- Function : Author
Nurhan Seyahi
- Function : Author
- PersonId : 1210112
- ORCID : 0000-0001-7427-618X
Hakki Arikan
- Function : Author
Mehmet Koc
- Function : Author
- PersonId : 1210113
- ORCID : 0000-0002-1433-8403
Taner Basturk
- Function : Author
Gonca Karahan
- Function : Author
Sebahat Usta Akgul
- Function : Author
- PersonId : 1210114
- ORCID : 0000-0003-0176-3344
Mehmet Sukru Sever
- Function : Author
Dan Zhang
- Function : Author
Domenico Santoro
- Function : Author
- PersonId : 1210115
- ORCID : 0000-0002-4279-6559
Mario Bonomini
- Function : Author
Francesco Londrino
- Function : Author
Loreto Gesualdo
- Function : Author
Jana Reiterova
- Function : Author
Vladimir Tesar
- Function : Author
- PersonId : 1210116
- ORCID : 0000-0001-6982-0689
Claudia Izzi
- Function : Author
Silvana Savoldi
- Function : Author
Donatella Spotti
- Function : Author
Carmelita Marcantoni
- Function : Author
Piergiorgio Messa
- Function : Author
Marco Galliani
- Function : Author
Dario Roccatello
- Function : Author
Simona Granata
- Function : Author
Gianluigi Zaza
- Function : Author
- PersonId : 1210117
- ORCID : 0000-0002-6004-6196
Francesca Lugani
- Function : Author
Gianmarco Ghiggeri
- Function : Author
Isabella Pisani
- Function : Author
Landino Allegri
- Function : Author
Ben Sprangers
- Function : Author
Jin-Ho Park
- Function : Author
- PersonId : 1210118
- ORCID : 0000-0002-3942-6813
Belong Cho
- Function : Author
Yon Su Kim
- Function : Author
Dong Ki Kim
- Function : Author
Hitoshi Suzuki
- Function : Author
- PersonId : 1210119
- ORCID : 0000-0002-1901-2111
Antonio Amoroso
- Function : Author
- PersonId : 1210120
- ORCID : 0000-0002-9437-9407
Daniel Cattran
- Function : Author
Fernando Fervenza
- Function : Author
Antonello Pani
- Function : Author
Patrick Hamilton
- Function : Author
Shelly Harris
- Function : Author
Sanjana Gupta
- Function : Author
Chris Cheshire
- Function : Author
Stephanie Dufek
- Function : Author
- PersonId : 1210121
- ORCID : 0000-0002-6323-6673
Naomi Issler
- Function : Author
Ruth Pepper
- Function : Author
John Connolly
- Function : Author
Stephen Powis
- Function : Author
Detlef Bockenhauer
- Function : Author
Horia Stanescu
- Function : Author
Neil Ashman
- Function : Author
Ruth Loos
- Function : Author
- PersonId : 1210122
- ORCID : 0000-0002-8532-5087
Eimear Kenny
- Function : Author
Matthias Wuttke
- Function : Author
- PersonId : 1210123
- ORCID : 0000-0003-3420-5082
Kai-Uwe Eckardt
- Function : Author
Anna Köttgen
- Function : Author
- PersonId : 1210124
- ORCID : 0000-0002-4671-3714
Julia Hofstra
- Function : Author
Marieke Coenen
- Function : Author
Lambertus Kiemeney
- Function : Author
Shreeram Akilesh
- Function : Author
- PersonId : 1210125
- ORCID : 0000-0003-3152-7991
Matthias Kretzler
- Function : Author
- PersonId : 1210126
- ORCID : 0000-0003-4064-0582
Lawrence Beck
- Function : Author
Benedicte Stengel
- Function : Author
Hanna Debiec
- Function : Author
Pierre Ronco
- Function : Author
- PersonId : 949869
Jack Wetzels
- Function : Author
- PersonId : 1210103
- ORCID : 0000-0002-0650-6921
Magdalena Zoledziewska
- Function : Author
Francesco Cucca
- Function : Author
- PersonId : 1176134
- ORCID : 0000-0002-7414-1995
Iuliana Ionita-Laza
- Function : Author
Hajeong Lee
- Function : Author
Elion Hoxha
- Function : Author
Rolf Stahl
- Function : Author
Paul Brenchley
- Function : Author
Francesco Scolari
- Function : Author
Ming-Hui Zhao
- Function : Author
- PersonId : 1210127
- ORCID : 0000-0003-3340-3108
Ali Gharavi
- Function : Author
- PersonId : 1210128
- ORCID : 0000-0003-2801-233X
Robert Kleta
- Function : Author
- PersonId : 1210129
- ORCID : 0000-0002-0228-8656
Nan Chen
- Function : Author
Krzysztof Kiryluk
- Function : Author
- PersonId : 1210130
- ORCID : 0000-0002-5047-6715
Abstract
Abstract 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.