PT  - JOURNAL ARTICLE
AU  - Xianyong Yin
AU  - Kwangwoo Kim
AU  - Hiroyuki Suetsugu
AU  - So-Young Bang
AU  - Leilei Wen
AU  - Masaru Koido
AU  - Eunji Ha
AU  - Lu Liu
AU  - Yuma Sakamoto
AU  - Sungsin Jo
AU  - Rui-Xue Leng
AU  - Nao Otomo
AU  - Young-Chang Kwon
AU  - Yujun Sheng
AU  - Nobuhiko Sugano
AU  - Mi Yeong Hwang
AU  - Weiran Li
AU  - Masaya Mukai
AU  - Kyungheon Yoon
AU  - Minglong Cai
AU  - Kazuyoshi Ishigaki
AU  - Won Tae Chung
AU  - He Huang
AU  - Daisuke Takahashi
AU  - Shin-Seok Lee
AU  - Mengwei Wang
AU  - Kohei Karino
AU  - Seung-Cheol Shim
AU  - Xiaodong Zheng
AU  - Tomoya Miyamura
AU  - Young Mo Kang
AU  - Dongqing Ye
AU  - Junichi Nakamura
AU  - Chang-Hee Suh
AU  - Yuanjia Tang
AU  - Goro Motomura
AU  - Yong-Beom Park
AU  - Huihua Ding
AU  - Takeshi Kuroda
AU  - Jung-Yoon Choe
AU  - Chengxu Li
AU  - Hiroaki Niiro
AU  - Youngho Park
AU  - Changbing Shen
AU  - Takeshi Miyamoto
AU  - Ga-Young Ahn
AU  - Wenmin Fei
AU  - Tsutomu Takeuchi
AU  - Jung-Min Shin
AU  - Keke Li
AU  - Yasushi Kawaguchi
AU  - Yeon-Kyung Lee
AU  - Yong-Fei Wang
AU  - Koichi Amano
AU  - Dae Jin Park
AU  - Wanling Yang
AU  - Yoshifumi Tada
AU  - Yu Lung Lau
AU  - Ken Yamaji
AU  - Zhengwei Zhu
AU  - Masato Shimizu
AU  - Takashi Atsumi
AU  - Akari Suzuki
AU  - Takayuki Sumida
AU  - Yukinori Okada
AU  - Koichi Matsuda
AU  - Keitaro Matsuo
AU  - Yuta Kochi
AU  - Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head
AU  - Kazuhiko Yamamoto
AU  - Koichiro Ohmura
AU  - Tae-Hwan Kim
AU  - Sen Yang
AU  - Takuaki Yamamoto
AU  - Bong-Jo Kim
AU  - Nan Shen
AU  - Shiro Ikegawa
AU  - Hye-Soon Lee
AU  - Xuejun Zhang
AU  - Chikashi Terao
AU  - Yong Cui
AU  - Sang-Cheol Bae
TI  - Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study
AID  - 10.1136/annrheumdis-2022-222345
DP  - 2022 Sep 01
TA  - Annals of the Rheumatic Diseases
PG  - 1273--1280
VI  - 81
IP  - 9
4099  - http://ard.bmj.com/content/81/9/1273.short
4100  - http://ard.bmj.com/content/81/9/1273.full
SO  - Ann Rheum Dis2022 Sep 01; 81
AB  - 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.Data are available upon reasonable request. The ATAC-seq data for human blood B and T cells have been deposited with the China National Genomics Data Center (https://bigd.big.ac.cn/gsa-human/browse) under accession no. HRA000271. The expression quantitative trait loci summary-level data in blood immune cells are publicly available from our website (JENGER; http://jenger.riken.jp/en/). All the other data relevant to the study are included in the article or uploaded as supplementary information. The meta-analysis summary association statistics in the current study are available from the corresponding author on reasonable request.