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; Donatella Spotti; Piergiorgio Messa; Francesca Lugani; Gian Marco Ghiggeri

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, Donatella Spotti, Piergiorgio Messa, Francesca Lugani, Gian Marco Ghiggeri

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
Article number	1600
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15383-w
Publication status	Published - Dec 1 2020

ASJC Scopus subject areas

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

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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., ... Ghiggeri, G. M. (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

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. / Xie, Jingyuan; Liu, Lili; Mladkova, Nikol; Li, Yifu; Ren, Hong; Wang, Weiming; Cui, Zhao; Lin, Li; Hu, Xiaofan; Yu, Xialian; Xu, Jing; Liu, Gang; Caliskan, Yasar; Sidore, Carlo; Balderes, Olivia; Rosen, Raphael J.; Bodria, Monica; Zanoni, Francesca; Zhang, Jun Y.; Krithivasan, Priya; Mehl, Karla; Marasa, Maddalena; Khan, Atlas; Ozay, Fatih; Canetta, Pietro A.; Bomback, Andrew S.; Appel, Gerald B.; Sanna-Cherchi, Simone; Sampson, Matthew G.; Mariani, Laura H.; Perkowska-Ptasinska, Agnieszka; Durlik, Magdalena; Mucha, Krzysztof; Moszczuk, Barbara; Foroncewicz, Bartosz; Pączek, Leszek; Habura, Ireneusz; Ars, Elisabet; Ballarin, Jose; Mani, Laila Yasmin; Vogt, Bruno; Ozturk, Savas; Yildiz, Abdülmecit; Seyahi, Nurhan; Arikan, Hakki; Koc, Mehmet; Spotti, Donatella; Messa, Piergiorgio ; Lugani, Francesca ; Ghiggeri, Gian Marco.

In: Nature Communications, Vol. 11, No. 1, 1600, 01.12.2020.

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

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, Spotti, D, Messa, P , Lugani, F & Ghiggeri, GM 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

Xie, Jingyuan ; Liu, Lili ; Mladkova, Nikol ; Li, Yifu ; Ren, Hong ; Wang, Weiming ; Cui, Zhao ; Lin, Li ; Hu, Xiaofan ; Yu, Xialian ; Xu, Jing ; Liu, Gang ; Caliskan, Yasar ; Sidore, Carlo ; Balderes, Olivia ; Rosen, Raphael J. ; Bodria, Monica ; Zanoni, Francesca ; Zhang, Jun Y. ; Krithivasan, Priya ; Mehl, Karla ; Marasa, Maddalena ; Khan, Atlas ; Ozay, Fatih ; Canetta, Pietro A. ; Bomback, Andrew S. ; Appel, Gerald B. ; Sanna-Cherchi, Simone ; Sampson, Matthew G. ; Mariani, Laura H. ; Perkowska-Ptasinska, Agnieszka ; Durlik, Magdalena ; Mucha, Krzysztof ; Moszczuk, Barbara ; Foroncewicz, Bartosz ; Pączek, Leszek ; Habura, Ireneusz ; Ars, Elisabet ; Ballarin, Jose ; Mani, Laila Yasmin ; Vogt, Bruno ; Ozturk, Savas ; Yildiz, Abdülmecit ; Seyahi, Nurhan ; Arikan, Hakki ; Koc, Mehmet ; Spotti, Donatella ; Messa, Piergiorgio ; Lugani, Francesca ; Ghiggeri, Gian Marco. / The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. In: Nature Communications. 2020 ; Vol. 11, No. 1.

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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 Donatella Spotti and Piergiorgio Messa and Francesca Lugani and Ghiggeri, {Gian Marco}",

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AU - Wang, Weiming

AU - Cui, Zhao

AU - Lin, Li

AU - Hu, Xiaofan

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AU - Caliskan, Yasar

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AU - Zanoni, Francesca

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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.

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AU - Mucha, Krzysztof

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AU - Yildiz, Abdülmecit

AU - Seyahi, Nurhan

AU - Arikan, Hakki

AU - Koc, Mehmet

AU - Spotti, Donatella

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AU - Lugani, Francesca

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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.

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

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