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Original ArticlesGenetics
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Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese

Xu-jie Zhou, Lam C. Tsoi, Yong Hu, Matthew T. Patrick, Kevin He, Celine C. Berthier, Yanming Li, Yan-na Wang, Yuan-yuan Qi, Yue-miao Zhang, Ting Gan, Yang Li, Ping Hou, Li-jun Liu, Su-fang Shi, Ji-cheng Lv, Hu-ji Xu and Hong Zhang
CJASN February 2021, 16 (2) 213-224; DOI: https://doi.org/10.2215/CJN.06910520
Xu-jie Zhou
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Lam C. Tsoi
5Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
6Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
7Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
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Yong Hu
8Beijing Institute of Biotechnology, Beijing, People’s Republic of China
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Matthew T. Patrick
5Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan
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Kevin He
9Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
10Kidney Epidemiology and Cost Center, School of Public Health, University of Michigan, Ann Arbor, Michigan
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Celine C. Berthier
11Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Yanming Li
12Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas
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Yan-na Wang
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Yuan-yuan Qi
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Yue-miao Zhang
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Ting Gan
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Yang Li
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Ping Hou
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Li-jun Liu
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Su-fang Shi
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Ji-cheng Lv
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Hu-ji Xu
12Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas
14Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China
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Hong Zhang
1Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China
2Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People’s Republic of China
3Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China
4Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
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Abstract

Background and objectives IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy.

Design, setting, participants, & measurements We performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored.

Results We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta<5×10−5) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy.

Conclusions Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.

  • IgA nephropathy
  • exome
  • exome-wide association study
  • genetic variants
  • differential expression
  • gene network
  • Received May 7, 2020.
  • Accepted December 11, 2020.
  • Copyright © 2021 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 16 (2)
Clinical Journal of the American Society of Nephrology
Vol. 16, Issue 2
February 08, 2021
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Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese
Xu-jie Zhou, Lam C. Tsoi, Yong Hu, Matthew T. Patrick, Kevin He, Celine C. Berthier, Yanming Li, Yan-na Wang, Yuan-yuan Qi, Yue-miao Zhang, Ting Gan, Yang Li, Ping Hou, Li-jun Liu, Su-fang Shi, Ji-cheng Lv, Hu-ji Xu, Hong Zhang
CJASN Feb 2021, 16 (2) 213-224; DOI: 10.2215/CJN.06910520

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Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese
Xu-jie Zhou, Lam C. Tsoi, Yong Hu, Matthew T. Patrick, Kevin He, Celine C. Berthier, Yanming Li, Yan-na Wang, Yuan-yuan Qi, Yue-miao Zhang, Ting Gan, Yang Li, Ping Hou, Li-jun Liu, Su-fang Shi, Ji-cheng Lv, Hu-ji Xu, Hong Zhang
CJASN Feb 2021, 16 (2) 213-224; DOI: 10.2215/CJN.06910520
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