Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis

Abstract

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4⁺CD25^–IL17⁺ Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN.

Keywords

IgA nephropathy (IgAN) / genome-wide association study (GWAS) / relevant cell types / integrative analysis / pleiotropy

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Acknowledgements

We are grateful to all the subjects and healthy volunteers who participated in this work. We thank Professor Jianjun Liu for reviewing the article and providing constructive suggestions. This work was supported by Guangdong–Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases (No. 2019B121205005), National Natural Science Foundation of China (Nos. 81920108008, 81770661, 82170714, and 82003561), Guangzhou Municipal Science and Technology Project of China (No. 202201011246), Basic and Applied Basic Research Foundation of Guangdong Province (No. 2021A1515111054) and Fundamental Research Funds for the Central Universities (No. 2019kfyXJJS036).

Compliance with ethics guidelines

Conflicts of interest Ming Li , Xingjie Hao, Dianchun Shi, Shanshan Cheng, Zhong Zhong, Lu Cai, Minghui Jiang, Lin Ding, Lanbo Ding, Chaolong Wang, and Xueqing Yu declare that they have no conflict of interest.

The study was approved by the Institutional Review Board at the Guangdong Provincial People’s Hospital (No. GDREC2019272H) and the First Affiliated Hospital of Sun Yat-sen University (No. 2016215) according to the Declaration of Helsinki and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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