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; Xiaofan Hu; Xialian Yu; Gang Liu; Yasar Caliskan; Carlo Sidore; Olivia Balderes; Raphael J Rosen; Monica Bodria; Francesca Zanoni; 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; Patrick Hamilton; Robert Kleta; Paul Brenchley

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, Xiaofan Hu, Xialian Yu, Gang Liu, Yasar Caliskan, Carlo Sidore, Olivia Balderes, Raphael J Rosen, Monica Bodria, Francesca Zanoni, Priya Krithivasan, Karla Mehl, Maddalena Marasa, Atlas KhanFatih 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, Patrick Hamilton, Robert Kleta, Paul Brenchley

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

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
Pages (from-to)	1600
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15383-w
Publication status	Published - 30 Mar 2020

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

@article{2fc44a929289426fa48c0dee44b13c92,

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 Xiaofan Hu and Xialian Yu and Gang Liu and Yasar Caliskan and Carlo Sidore and Olivia Balderes and Rosen, {Raphael J} and Monica Bodria and Francesca Zanoni 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 Laila-Yasmin Mani 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 Patrick Hamilton and Robert Kleta and Paul Brenchley",

year = "2020",

month = mar,

day = "30",

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

language = "English",

volume = "11",

pages = "1600",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

number = "1",

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Xie, J, Liu, L, Mladkova, N, Li, Y, Ren, H, Wang, W, Cui, Z, Hu, X, Yu, X, Liu, G, Caliskan, Y, Sidore, C, Balderes, O, Rosen, RJ, Bodria, M, Zanoni, F, 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, L-Y, Vogt, B, Ozturk, S, Yildiz, A, Seyahi, N, Arikan, H, Koc, M, Basturk, T, Karahan, G, Akgul, SU, Sever, MS, Zhang, D, Hamilton, P, Kleta, R & Brenchley, P 2020, 'The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis', Nature Communications, vol. 11, no. 1, pp. 1600. https://doi.org/10.1038/s41467-020-15383-w

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 - Hu, Xiaofan

AU - Yu, Xialian

AU - Liu, Gang

AU - Caliskan, Yasar

AU - Sidore, Carlo

AU - Balderes, Olivia

AU - Rosen, Raphael J

AU - Bodria, Monica

AU - Zanoni, Francesca

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 - Hamilton, Patrick

AU - Kleta, Robert

AU - Brenchley, Paul

PY - 2020/3/30

Y1 - 2020/3/30

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.

U2 - 10.1038/s41467-020-15383-w

DO - 10.1038/s41467-020-15383-w

M3 - Article

C2 - 32231244

SN - 2041-1723

VL - 11

SP - 1600

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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