TitleBiological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study
AuthorsYin, 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
AffiliationAnhui Med Univ, Affiliated Hosp 1, Dept Dermatol, Hefei, Anhui, Peoples R China
Anhui Med Univ, Inst Dermatol, Affiliated Hosp 1, Hefei, Anhui, Peoples R China
Anhui Med Univ, Key Lab Dermatol, Minist Educ, Hefei, Anhui, Peoples R China
Inflammat & Immune Mediated Dis Lab Anhui Prov, Hefei, Anhui, Peoples R China
China Japan Friendship Hosp, Dept Dermatol, Beijing, Peoples R China
Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA
Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA
Fudan Univ, Human Phenome Inst, Shanghai, Peoples R China
Kyung Hee Univ, Dept Biol, Seoul, South Korea
Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, Seoul, South Korea
RIKEN Ctr Med Sci, Lab Bone & Joint Dis, Tokyo, Japan
RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet Anal, Yokohama, Kanagawa, Japan
Kyushu Univ, Grad Sch Med Sci, Dept Orthopaed Surg, Fukuoka, Japan
Hanyang Univ, Dept Rheumatol, Hosp Rheumat Dis, Seoul, South Korea
Hanyang Univ, Inst Rheumatol Res, Seoul, South Korea
Univ Tokyo, Inst Med Sci, Dept Canc Biol, Div Mol Pathol, Tokyo, Japan
Koga Hosp 21, Kurume, Fukuoka, Japan
Anhui Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Hefei, Anhui, Peoples R China
Keio Univ, Dept Orthoped Surg, Sch Med, Tokyo, Japan
Osaka Univ, Dept Orthopaed Med Engn, Grad Sch Med, Osaka, Japan
Natl Inst Hlth, Dept Precis Med, Div Genome Sci, Cheongju, South Korea
Sapporo City Gen Hosp, Dept Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan
Harvard Med Sch, Div Genet, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA
Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA
Harvard Med Sch, Ctr Data Sci, Boston, MA 02115 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Dong A Univ Hosp, Dept Internal Med, Busan, South Korea
Hokkaido Univ, Fac Med, Dept Orthopaed Surg, Sapporo, Hokkaido, Japan
Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan
Chonnam Natl Univ, Dept Internal Med, Div Rheumatol, Med Sch & Hosp, Gwangju, South Korea
Hokkaido Univ, Fac Med, Dept Rheumatol Endocrinol & Nephrol, Sapporo, Hokkaido, Japan
Chungnam Natl Univ Hosp, Dept Internal Med, Div Rheumatol, Daejeon, South Korea
Natl Hosp Org, Kyushu Med Ctr, Dept Internal Med & Rheumatol, Fukuoka, Japan
Kyungpook Natl Univ Hosp, Dept Internal Med, Div Rheumatol, Daegu, South Korea
Chiba Univ, Grad Sch Med, Dept Orthopaed Surg, Chiba, Japan
Ajou Univ, Dept Rheumatol, Sch Med, Suwon, South Korea
Shanghai Jiao Tong Univ, Renji Hosp, Sch Med SJTUSM, Shanghai Inst Rheumatol, Shanghai, Peoples R China
Yonsei Univ, Dept Internal Med, Coll Med, Seoul, South Korea
Niigata Univ, Hlth Adm Ctr, Niigata, Japan
Catholic Univ Daegu, Dept Rheumatol, Sch Med, Daegu, South Korea
Kyushu Univ, Dept Med Educ, Grad Sch Med Sci, Fukuoka, Japan
Peking Univ, Dept Dermatol, Shenzhen Hosp, Shenzhen, Guangdong, Peoples R China
Shenzhen Peking Univ Hong Kong Univ Sci & Technol, Shenzhen Key Lab Translat Med Dermatol, Shenzhen, Guangdong, Peoples R China
Kumamoto Univ, Fac Life Sci, Dept Orthopaed Surg, Kumamoto, Japan
Keio Univ, Dept Internal Med, Div Rheumatol, Sch Med, Tokyo, Japan
Tokyo Womens Med Univ, Inst Rheumatol, Tokyo, Japan
Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Peoples R China
Saitama Med Univ, Saitama Med Ctr, Dept Rheumatol & Clin Immunol, Saitama, Japan
Saga Univ, Fac Med, Dept Rheumatol, Saga, Japan
Juntendo Univ, Dept Internal Med & Rheumatol, Sch Med, Tokyo, Japan
Hokkaido Med Ctr Rheumat Dis, Sapporo, Hokkaido, Japan
Showa Univ, Dept Orthopaed Surg, Sch Med, Tokyo, Japan
RIKEN Ctr Integrat Med Sci, Lab Autoimmune Dis, Yokohama, Kanagawa, Japan
Univ Tsukuba, Fac Med, Dept Internal Med, Ibaraki, Japan
Osaka Univ, Dept Stat Genet, Grad Sch Med, Osaka, Japan
Univ Tokyo, Grad Sch Med, Dept Genome Informat, Tokyo, Japan
RIKEN Ctr Integrat Med Sci, Lab Syst Genet, Yokohama, Kanagawa, Japan
Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab Genome Technol, Tokyo, Japan
Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Clin Genome Sequencing, Tokyo, Japan
Aichi Canc Ctr Res Inst, Div Canc Epidemiol & Prevent, Nagoya, Aichi, Japan
Nagoya Univ, Dept Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan
Tokyo Med & Dent Univ, Med Res Inst, Dept Genom Funct & Divers, Tokyo, Japan
Kyoto Univ, Dept Rheumatol & Clin Immunol, Grad Sch Med, Kyoto, Japan
Fukuoka Univ, Fac Med, Dept Orthopaed Surg, Fukuoka, Japan
Shanghai Jiao Tong Univ Sch Med SJTUSM, Renji Hosp, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes, Shanghai, Peoples R China
Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA
Fudan Univ, Huashan Hosp, Inst Dermatol, Dept Dermatol, Shanghai, Peoples R China
Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan
Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan
KeywordsRISK LOCI
CHROMATIN
PATHWAYS
PROTEINS
AFRICAN
GENE
Issue DateMay-2022
PublisherANNALS OF THE RHEUMATIC DISEASES
AbstractObjective 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<1.0x10(-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<7.7x10(-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=4.5x10(-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.
URIhttp://hdl.handle.net/20.500.11897/647031
ISSN0003-4967
DOI10.1136/annrheumdis-2022-222345
IndexedSCI(E)
Appears in Collections:深圳医院

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