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 - Spotti, Donatella
AU - Messa, Piergiorgio
AU - Lugani, Francesca
AU - Ghiggeri, Gian Marco
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.
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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
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1600
ER -