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Meta-analysis of 208,370 East Asians identifies 113 genomic loci and yields new non-immune cell relevant biological insights for systemic lupus erythematosus

By 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, Viktoryia Laurynenka, 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, Yongfei Wang, Koichi Amano, Wanling Yang, Yoshifumi Tada, Ken Yamaji, Masato Shimizu, Takashi Atsumi, Akari Suzuki, Takayuki Sumida, Yukinori Okada, Koichi Matsuda, Keitaro Matsuo, Yuta Kochi, Japanese Research Committee on Idiopathic Osteone, Leah C. Kottyan, Matthew T Weirauch, Sreeja Parameswaran, Shruti Eswar, Hanan Salim, Xiaoting Chen, Kazuhiko Yamamoto, John B. Harley, 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

Posted 25 Aug 2020
medRxiv DOI: 10.1101/2020.08.22.20178939

Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci1-8. Nevertheless, these loci only partially explain SLE heritability and provide limited biological insight. We report the largest study of SLE in East Asians (13,377 cases and 194,993 controls), identifying 233 association signals within 113 (46 novel) genetic loci. We detect six new lead missense variants and prioritize ten most likely putative causal variants, one of which we demonstrate exhibits allele-specific regulatory effect on ACAP1 in vitro. We suggest 677 effector genes with potential for drug repurposing, and provide evidence that two distinct association signals at a single locus act on different genes (NCF2 and SMG7). We demonstrate that SLE-risk variants overlap with cell-specific active regulatory elements, notably EBNA2-mediated super-enhancers in Epstein-Barr Virus-transformed B cells, and implicate the role for non-immune cells in SLE biology. These findings shed light on genetic and biological understandings of SLE.

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