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