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

Abstract

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.

• Authors: 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 Cai, Kazuyoshi 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, Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head, 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
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 81 Issue 9 Pg. 1273-1280 (Aug 11 2022) ISSN: 1468-2060 [Electronic] England
• PMID: 35609976 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.