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, 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
Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China.
Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China.
Ann Rheum Dis. 2022 Aug 11;81(9):1273-1280. doi: 10.1136/annrheumdis-2022-222345.
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.
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.
TWAS identified 171 genes for SLE (p<1.0×10); 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 and SLE (p<7.7×10). 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) around . 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 , and that presence of the SLE risk allele decreased expression.
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.
全基因组关联研究（GWAS）已确定了超过100个系统性红斑狼疮（SLE）的风险位点，但大多数位点的致病基因仍不清楚，这阻碍了这些遗传学发现的转化应用。我们旨在对在最新的东亚GWAS荟萃分析中确定的110个SLE位点的潜在基因进行优先级排序。
我们在105名日本个体的血液B细胞、CD4和CD8 T细胞、单核细胞、自然杀伤细胞和外周血细胞中构建了基因表达预测模型。我们使用来自208370名东亚人的最新全基因组关联荟萃分析的数据进行了全转录组关联研究（TWAS），并使用TWAS和三种数据驱动的计算方法寻找候选基因。
TWAS确定了171个SLE相关基因（p<1.0×10）；114个（66.7%）仅在单一细胞类型中显示出显著性；127个（74.3%）位于SLE GWAS位点。TWAS确定了[具体基因]与SLE之间的强关联（p<7.7×10）。对现有的208370名东亚人以及另外1498例病例和3330例对照的遗传关联进行荟萃分析，发现在[具体基因]周围的rs72836542处有一个新的单变体关联（OR=1.11，p=4.5×10）。对于110个SLE位点，我们确定了276个候选基因，包括最近确定的SLE新位点中的104个基因。我们在体外证明，假定的因果变体rs61759532对[具体基因]表现出等位基因特异性调控作用，并且SLE风险等位基因的存在降低了[具体基因]的表达。
六种免疫细胞类型的细胞水平TWAS补充了SLE基因发现，并指导了新遗传关联的鉴定。这些基因发现为SLE遗传关联提供了生物学见解。
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