The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Jingyuan Xie; Lili Liu; Nikol Mladkova; Yifu Li; Hong Ren; Weiming Wang; Zhao Cui; Li Lin; Xiaofan Hu; Xialian Yu; Jing Xu; Gang Liu; Yasar Caliskan; Carlo Sidore; Olivia Balderes; Raphael J. Rosen; Monica Bodria; Francesca Zanoni; Jun Y. Zhang; Priya Krithivasan; Karla Mehl; Maddalena Marasa; Atlas Khan; Fatih Ozay; Pietro A. Canetta; Andrew S. Bomback; Gerald B. Appel; Simone Sanna-Cherchi; Matthew G. Sampson; Laura H. 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; Gian Marco Ghiggeri; Isabella Pisani; Landino Allegri; Ben Sprangers; Jin Ho Park; Be Long Cho; Yon Su Kim; Dong Ki Kim; Hitoshi Suzuki; Antonio Amoroso; Daniel C. Cattran; Fernando C. Fervenza; Antonello Pani; Patrick Hamilton; Shelly Harris; Sanjana Gupta; Chris Cheshire; Stephanie Dufek; Naomi Issler; Ruth J. Pepper; John Connolly; Stephen Powis; Detlef Bockenhauer; Horia C. Stanescu; Neil Ashman; Ruth J.F. Loos; Eimear E. Kenny; Matthias Wuttke; Kai Uwe Eckardt; Anna Köttgen; Julia M. Hofstra; Marieke J.H. Coenen; Lambertus A. Kiemeney; Shreeram Akilesh; Matthias Kretzler; Lawrence H. Beck; Benedicte Stengel; Hanna Debiec; Pierre Ronco; Jack F.M. Wetzels; Magdalena Zoledziewska; Francesco Cucca; Iuliana Ionita-Laza; Hajeong Lee; Elion Hoxha; Rolf A.K. Stahl; Paul Brenchley; Francesco Scolari; Ming hui Zhao; Ali G. Gharavi; Robert Kleta; Nan Chen; Krzysztof Kiryluk

doi:10.1038/s41467-020-15383-w

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Jingyuan Xie, Lili Liu, Nikol Mladkova, Yifu Li, Hong Ren, Weiming Wang, Zhao Cui, Li Lin, Xiaofan Hu, Xialian Yu, Jing Xu, Gang Liu, Yasar Caliskan, Carlo Sidore, Olivia Balderes, Raphael J. Rosen, Monica Bodria, Francesca Zanoni, Jun Y. Zhang, Priya KrithivasanKarla Mehl, Maddalena Marasa, Atlas Khan, Fatih Ozay, Pietro A. Canetta, Andrew S. Bomback, Gerald B. Appel, Simone Sanna-Cherchi, Matthew G. Sampson, Laura H. 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, Gian Marco Ghiggeri, Isabella Pisani, Landino Allegri, Ben Sprangers, Jin Ho Park, Be Long Cho, Yon Su Kim, Dong Ki Kim, Hitoshi Suzuki, Antonio Amoroso, Daniel C. Cattran, Fernando C. Fervenza, Antonello Pani, Patrick Hamilton, Shelly Harris, Sanjana Gupta, Chris Cheshire, Stephanie Dufek, Naomi Issler, Ruth J. Pepper, John Connolly, Stephen Powis, Detlef Bockenhauer, Horia C. Stanescu, Neil Ashman, Ruth J.F. Loos, Eimear E. Kenny, Matthias Wuttke, Kai Uwe Eckardt, Anna Köttgen, Julia M. Hofstra, Marieke J.H. Coenen, Lambertus A. Kiemeney, Shreeram Akilesh, Matthias Kretzler, Lawrence H. Beck, Benedicte Stengel, Hanna Debiec, Pierre Ronco, Jack F.M. Wetzels, Magdalena Zoledziewska, Francesco Cucca, Iuliana Ionita-Laza, Hajeong Lee, Elion Hoxha, Rolf A.K. Stahl, Paul Brenchley, Francesco Scolari, Ming hui Zhao, Ali G. Gharavi, Robert Kleta, Nan Chen, Krzysztof Kiryluk

Nephrology and Hypertension

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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.

Original language	English (US)
Article number	1600
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15383-w
State	Published - Dec 1 2020

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1038/s41467-020-15383-w

Cite this

Xie, J., Liu, L., Mladkova, N., Li, Y., Ren, H., Wang, W., Cui, Z., Lin, L., Hu, X., Yu, X., Xu, J., Liu, G., Caliskan, Y., Sidore, C., Balderes, O., Rosen, R. J., Bodria, M., Zanoni, F., Zhang, J. Y., ... Kiryluk, K. (2020). The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. Nature communications, 11(1), Article 1600. https://doi.org/10.1038/s41467-020-15383-w

Xie, J, Liu, L, Mladkova, N, Li, Y, Ren, H, Wang, W, Cui, Z, Lin, L, Hu, X, Yu, X, Xu, J, Liu, G, Caliskan, Y, Sidore, C, Balderes, O, Rosen, RJ, Bodria, M, Zanoni, F, Zhang, JY, Krithivasan, P, Mehl, K, Marasa, M, Khan, A, Ozay, F, Canetta, PA, Bomback, AS, Appel, GB, Sanna-Cherchi, S, Sampson, MG, Mariani, LH, Perkowska-Ptasinska, A, Durlik, M, Mucha, K, Moszczuk, B, Foroncewicz, B, Pączek, L, Habura, I, Ars, E, Ballarin, J, Mani, LY, Vogt, B, Ozturk, S, Yildiz, A, Seyahi, N, Arikan, H, Koc, M, Basturk, T, Karahan, G, Akgul, SU, Sever, MS, Zhang, D, Santoro, D, Bonomini, M, Londrino, F, Gesualdo, L, Reiterova, J, Tesar, V, Izzi, C, Savoldi, S, Spotti, D, Marcantoni, C, Messa, P, Galliani, M, Roccatello, D, Granata, S, Zaza, G, Lugani, F, Ghiggeri, GM, Pisani, I, Allegri, L, Sprangers, B, Park, JH, Cho, BL, Kim, YS, Kim, DK, Suzuki, H, Amoroso, A, Cattran, DC, Fervenza, FC, Pani, A, Hamilton, P, Harris, S, Gupta, S, Cheshire, C, Dufek, S, Issler, N, Pepper, RJ, Connolly, J, Powis, S, Bockenhauer, D, Stanescu, HC, Ashman, N, Loos, RJF, Kenny, EE, Wuttke, M, Eckardt, KU, Köttgen, A, Hofstra, JM, Coenen, MJH, Kiemeney, LA, Akilesh, S, Kretzler, M, Beck, LH, Stengel, B, Debiec, H, Ronco, P, Wetzels, JFM, Zoledziewska, M, Cucca, F, Ionita-Laza, I, Lee, H, Hoxha, E, Stahl, RAK, Brenchley, P, Scolari, F, Zhao, MH, Gharavi, AG, Kleta, R, Chen, N & Kiryluk, K 2020, 'The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis', Nature communications, vol. 11, no. 1, 1600. https://doi.org/10.1038/s41467-020-15383-w

@article{c3717d69efef4973b0f89b250b311267,

title = "The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis",

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.",

author = "Jingyuan Xie and Lili Liu and Nikol Mladkova and Yifu Li and Hong Ren and Weiming Wang and Zhao Cui and Li Lin and Xiaofan Hu and Xialian Yu and Jing Xu and Gang Liu and Yasar Caliskan and Carlo Sidore and Olivia Balderes and Rosen, {Raphael J.} and Monica Bodria and Francesca Zanoni and Zhang, {Jun Y.} and Priya Krithivasan and Karla Mehl and Maddalena Marasa and Atlas Khan and Fatih Ozay and Canetta, {Pietro A.} and Bomback, {Andrew S.} and Appel, {Gerald B.} and Simone Sanna-Cherchi and Sampson, {Matthew G.} and Mariani, {Laura H.} and Agnieszka Perkowska-Ptasinska and Magdalena Durlik and Krzysztof Mucha and Barbara Moszczuk and Bartosz Foroncewicz and Leszek P{\c a}czek and Ireneusz Habura and Elisabet Ars and Jose Ballarin and Mani, {Laila Yasmin} and Bruno Vogt and Savas Ozturk and Abd{\"u}lmecit Yildiz and Nurhan Seyahi and Hakki Arikan and Mehmet Koc and Taner Basturk and Gonca Karahan and Akgul, {Sebahat Usta} and Sever, {Mehmet Sukru} and Dan Zhang and Domenico Santoro and Mario Bonomini and Francesco Londrino and Loreto Gesualdo and Jana Reiterova and Vladimir Tesar and Claudia Izzi and Silvana Savoldi and Donatella Spotti and Carmelita Marcantoni and Piergiorgio Messa and Marco Galliani and Dario Roccatello and Simona Granata and Gianluigi Zaza and Francesca Lugani and Ghiggeri, {Gian Marco} and Isabella Pisani and Landino Allegri and Ben Sprangers and Park, {Jin Ho} and Cho, {Be Long} and Kim, {Yon Su} and Kim, {Dong Ki} and Hitoshi Suzuki and Antonio Amoroso and Cattran, {Daniel C.} and Fervenza, {Fernando C.} and Antonello Pani and Patrick Hamilton and Shelly Harris and Sanjana Gupta and Chris Cheshire and Stephanie Dufek and Naomi Issler and Pepper, {Ruth J.} and John Connolly and Stephen Powis and Detlef Bockenhauer and Stanescu, {Horia C.} and Neil Ashman and Loos, {Ruth J.F.} and Kenny, {Eimear E.} and Matthias Wuttke and Eckardt, {Kai Uwe} and Anna K{\"o}ttgen and Hofstra, {Julia M.} and Coenen, {Marieke J.H.} and Kiemeney, {Lambertus A.} and Shreeram Akilesh and Matthias Kretzler and Beck, {Lawrence H.} and Benedicte Stengel and Hanna Debiec and Pierre Ronco and Wetzels, {Jack F.M.} and Magdalena Zoledziewska and Francesco Cucca and Iuliana Ionita-Laza and Hajeong Lee and Elion Hoxha and Stahl, {Rolf A.K.} and Paul Brenchley and Francesco Scolari and Zhao, {Ming hui} and Gharavi, {Ali G.} and Robert Kleta and Nan Chen and Krzysztof Kiryluk",

note = "Funding Information: We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project “Autoimmunity in Membranous Nephropathy”, grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/ 200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter{\textquoteright}s Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018–2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.). The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Pozna{\'n} University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3–1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012-ADG_20120314 grant 322947, 7th Framework Programme of the European Community contract 2012–305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-15383-w",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

AU - Xie, Jingyuan

AU - Liu, Lili

AU - Mladkova, Nikol

AU - Li, Yifu

AU - Ren, Hong

AU - Wang, Weiming

AU - Cui, Zhao

AU - Lin, Li

AU - Hu, Xiaofan

AU - Yu, Xialian

AU - Xu, Jing

AU - Liu, Gang

AU - Caliskan, Yasar

AU - Sidore, Carlo

AU - Balderes, Olivia

AU - Rosen, Raphael J.

AU - Bodria, Monica

AU - Zanoni, Francesca

AU - Zhang, Jun Y.

AU - Krithivasan, Priya

AU - Mehl, Karla

AU - Marasa, Maddalena

AU - Khan, Atlas

AU - Ozay, Fatih

AU - Canetta, Pietro A.

AU - Bomback, Andrew S.

AU - Appel, Gerald B.

AU - Sanna-Cherchi, Simone

AU - Sampson, Matthew G.

AU - Mariani, Laura H.

AU - Perkowska-Ptasinska, Agnieszka

AU - Durlik, Magdalena

AU - Mucha, Krzysztof

AU - Moszczuk, Barbara

AU - Foroncewicz, Bartosz

AU - Pączek, Leszek

AU - Habura, Ireneusz

AU - Ars, Elisabet

AU - Ballarin, Jose

AU - Mani, Laila Yasmin

AU - Vogt, Bruno

AU - Ozturk, Savas

AU - Yildiz, Abdülmecit

AU - Seyahi, Nurhan

AU - Arikan, Hakki

AU - Koc, Mehmet

AU - Basturk, Taner

AU - Karahan, Gonca

AU - Akgul, Sebahat Usta

AU - Sever, Mehmet Sukru

AU - Zhang, Dan

AU - Santoro, Domenico

AU - Bonomini, Mario

AU - Londrino, Francesco

AU - Gesualdo, Loreto

AU - Reiterova, Jana

AU - Tesar, Vladimir

AU - Izzi, Claudia

AU - Savoldi, Silvana

AU - Spotti, Donatella

AU - Marcantoni, Carmelita

AU - Messa, Piergiorgio

AU - Galliani, Marco

AU - Roccatello, Dario

AU - Granata, Simona

AU - Zaza, Gianluigi

AU - Lugani, Francesca

AU - Ghiggeri, Gian Marco

AU - Pisani, Isabella

AU - Allegri, Landino

AU - Sprangers, Ben

AU - Park, Jin Ho

AU - Cho, Be Long

AU - Kim, Yon Su

AU - Kim, Dong Ki

AU - Suzuki, Hitoshi

AU - Amoroso, Antonio

AU - Cattran, Daniel C.

AU - Fervenza, Fernando C.

AU - Pani, Antonello

AU - Hamilton, Patrick

AU - Harris, Shelly

AU - Gupta, Sanjana

AU - Cheshire, Chris

AU - Dufek, Stephanie

AU - Issler, Naomi

AU - Pepper, Ruth J.

AU - Connolly, John

AU - Powis, Stephen

AU - Bockenhauer, Detlef

AU - Stanescu, Horia C.

AU - Ashman, Neil

AU - Loos, Ruth J.F.

AU - Kenny, Eimear E.

AU - Wuttke, Matthias

AU - Eckardt, Kai Uwe

AU - Köttgen, Anna

AU - Hofstra, Julia M.

AU - Coenen, Marieke J.H.

AU - Kiemeney, Lambertus A.

AU - Akilesh, Shreeram

AU - Kretzler, Matthias

AU - Beck, Lawrence H.

AU - Stengel, Benedicte

AU - Debiec, Hanna

AU - Ronco, Pierre

AU - Wetzels, Jack F.M.

AU - Zoledziewska, Magdalena

AU - Cucca, Francesco

AU - Ionita-Laza, Iuliana

AU - Lee, Hajeong

AU - Hoxha, Elion

AU - Stahl, Rolf A.K.

AU - Brenchley, Paul

AU - Scolari, Francesco

AU - Zhao, Ming hui

AU - Gharavi, Ali G.

AU - Kleta, Robert

AU - Chen, Nan

AU - Kiryluk, Krzysztof

N1 - Funding Information: We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project “Autoimmunity in Membranous Nephropathy”, grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/ 200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter’s Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018–2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.). The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznań University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3–1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012-ADG_20120314 grant 322947, 7th Framework Programme of the European Community contract 2012–305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85082558400&partnerID=8YFLogxK

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U2 - 10.1038/s41467-020-15383-w

DO - 10.1038/s41467-020-15383-w

M3 - Article

C2 - 32231244

AN - SCOPUS:85082558400

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1600

ER -

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

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