Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

Xianyong Yin, Kwangwoo Kim, Hiroyuki Suetsugu, So Young Bang, Leilei Wen, Masaru Koido, Eunji Ha, Lu Liu, Yuma Sakamoto, Sungsin Jo, Rui Xue Leng, Nao Otomo, Young Chang Kwon, Yujun Sheng, Nobuhiko Sugano, Mi Yeong Hwang, Weiran Li, Masaya Mukai, Kyungheon Yoon, Minglong CaiKazuyoshi Ishigaki, Won Tae Chung, He Huang, Daisuke Takahashi, Shin Seok Lee, Mengwei Wang, Kohei Karino, Seung Cheol Shim, Xiaodong Zheng, Tomoya Miyamura, Young Mo Kang, Dongqing Ye, Junichi Nakamura, Chang Hee Suh, Yuanjia Tang, Goro Motomura, Yong Beom Park, Huihua Ding, Takeshi Kuroda, Jung Yoon Choe, Chengxu Li, Hiroaki Niiro, Youngho Park, Changbing Shen, Takeshi Miyamoto, Ga Young Ahn, Wenmin Fei, Tsutomu Takeuchi, Jung Min Shin, Keke Li, Yasushi Kawaguchi, Yeon Kyung Lee, Yong Fei Wang, Koichi Amano, Dae Jin Park, Wanling Yang, Yoshifumi Tada, Yu Lung Lau, Ken Yamaji, Zhengwei Zhu, Masato Shimizu, Takashi Atsumi, Akari Suzuki, Takayuki Sumida, Yukinori Okada, Koichi Matsuda, Keitaro Matsuo, Yuta Kochi, Kazuhiko Yamamoto, Koichiro Ohmura, Tae Hwan Kim, Sen Yang, Takuaki Yamamoto, Bong Jo Kim, Nan Shen, Shiro Ikegawa, Hye Soon Lee, Xuejun Zhang, Chikashi Terao, Yong Cui, Sang Cheol Bae

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0×10 -5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10 -8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 -9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Original languageEnglish
Pages (from-to)1273-1280
Number of pages8
JournalAnnals of the Rheumatic Diseases
Issue number9
Publication statusPublished - 2022 Sept 1

Bibliographical note

Publisher Copyright:
© 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • General Biochemistry,Genetics and Molecular Biology


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