Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

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; 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; Yong Fei Wang; Koichi Amano; Dae Jin Park; Wanling Yang; Yoshifumi Tada; Yu Lung Lau; Ken Yamaji; Zhengwei Zhu; Masato Shimizu; Takashi Atsumi; Akari Suzuki; Takayuki Sumida; Yukinori Okada; Koichi Matsuda; Keitaro Matsuo; Yuta Kochi; Kazuhiko Yamamoto; 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

doi:10.1136/annrheumdis-2022-222345

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

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, Young Chang Kwon, Yujun Sheng, Nobuhiko Sugano, Mi Yeong Hwang, Weiran Li, Masaya Mukai, Kyungheon Yoon, Minglong CaiKazuyoshi 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, Yong Fei Wang, Koichi Amano, Dae Jin Park, Wanling Yang, Yoshifumi Tada, Yu Lung Lau, Ken Yamaji, Zhengwei Zhu, Masato Shimizu, Takashi Atsumi, Akari Suzuki, Takayuki Sumida, Yukinori Okada, Koichi Matsuda, Keitaro Matsuo, Yuta Kochi, Kazuhiko Yamamoto, 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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1273-1280
Number of pages	8
Journal	Annals of the Rheumatic Diseases
Volume	81
Issue number	9
DOIs	https://doi.org/10.1136/annrheumdis-2022-222345
Publication status	Published - 2022 Sept 1

Bibliographical note

Funding Information:
Contributors XY, KKim and HS contributed equally to this work, and either has the right to list himself first in bibliographic documents. SCB, YC, CT, XZhang, XY, KKim and HS conceived the study design. SCB, YC, XZhang, SY, KKim and CT acquainted the financial support. XY, KKim, HS, CT, YC and SCB wrote the manuscript. XY, KKim, HS, EH, XZheng, and YW conducted all of the analyses with the help of KT, NO, MK, KI and CTerao, KKim, SYB, LW, LL, RXL, YSheng, MYH, WL, KYoon, MC, HH, MW, YTang, ZZ, HD, CL, CS, WF, KL, BJK, HSL, SCB, SH, YSakamoto, NSugano, MM, DT, KKarino, TMiyamura, JN, GM, TKuroda, HN, TMiyamoto, TT, YKawaguchi, KA, YTada, KYamaji, MS, TA, AS, TSumida, YOkada, KMatsuda, KMatsuo, YKochi, TSeki, YTanaka, TKubo, RH, TYoshioka, MY, TKabata, YA, YOhta, TO, YN, AK, YY, KOhzono, KYamamoto, KOhmura, TYamamoto and SI generated genetic data. LL and HH contributed to ATAC-seq experiment. SJ and THK performed luciferase reporter assays and EMSAs. SYB, SJ, YCK, WTC, SSL, SCS, YMK, DY, CHS, YBP, JYC, YP, GYA, JMS, YKL, DJP, WY, THK, SY, BJK, NShen, HSL, XZhang, CT and SCB managed the cohort data. SCB, YC and CT had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

All Science Journal Classification (ASJC) codes

Rheumatology
Immunology and Allergy
Immunology
Biochemistry, Genetics and Molecular Biology(all)

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10.1136/annrheumdis-2022-222345

Cite this

Yin, X., Kim, K., Suetsugu, H., Bang, S. Y., Wen, L., Koido, M., Ha, E., Liu, L., Sakamoto, Y., Jo, S., Leng, R. X., Otomo, N., Kwon, Y. C., Sheng, Y., Sugano, N., Hwang, M. Y., Li, W., Mukai, M., Yoon, K., ... Bae, S. C. (2022). Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study. Annals of the Rheumatic Diseases, 81(9), 1273-1280. https://doi.org/10.1136/annrheumdis-2022-222345

@article{c9f1d39d4c3243b3938fa95c4b901ba8,

title = "Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study",

abstract = "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.",

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

note = "Funding Information: Contributors XY, KKim and HS contributed equally to this work, and either has the right to list himself first in bibliographic documents. SCB, YC, CT, XZhang, XY, KKim and HS conceived the study design. SCB, YC, XZhang, SY, KKim and CT acquainted the financial support. XY, KKim, HS, CT, YC and SCB wrote the manuscript. XY, KKim, HS, EH, XZheng, and YW conducted all of the analyses with the help of KT, NO, MK, KI and CTerao, KKim, SYB, LW, LL, RXL, YSheng, MYH, WL, KYoon, MC, HH, MW, YTang, ZZ, HD, CL, CS, WF, KL, BJK, HSL, SCB, SH, YSakamoto, NSugano, MM, DT, KKarino, TMiyamura, JN, GM, TKuroda, HN, TMiyamoto, TT, YKawaguchi, KA, YTada, KYamaji, MS, TA, AS, TSumida, YOkada, KMatsuda, KMatsuo, YKochi, TSeki, YTanaka, TKubo, RH, TYoshioka, MY, TKabata, YA, YOhta, TO, YN, AK, YY, KOhzono, KYamamoto, KOhmura, TYamamoto and SI generated genetic data. LL and HH contributed to ATAC-seq experiment. SJ and THK performed luciferase reporter assays and EMSAs. SYB, SJ, YCK, WTC, SSL, SCS, YMK, DY, CHS, YBP, JYC, YP, GYA, JMS, YKL, DJP, WY, THK, SY, BJK, NShen, HSL, XZhang, CT and SCB managed the cohort data. SCB, YC and CT had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = sep,

day = "1",

doi = "10.1136/annrheumdis-2022-222345",

language = "English",

volume = "81",

pages = "1273--1280",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "9",

}

Yin, X, Kim, K, Suetsugu, H, Bang, SY, Wen, L, Koido, M, Ha, E, Liu, L, Sakamoto, Y, Jo, S, Leng, RX, Otomo, N, Kwon, YC, Sheng, Y, Sugano, N, Hwang, MY, Li, W, Mukai, M, Yoon, K, Cai, M, Ishigaki, K, Chung, WT, Huang, H, Takahashi, D, Lee, SS, Wang, M, Karino, K, Shim, SC, Zheng, X, Miyamura, T, Kang, YM, Ye, D, Nakamura, J, Suh, CH, Tang, Y, Motomura, G, Park, YB, Ding, H, Kuroda, T, Choe, JY, Li, C, Niiro, H, Park, Y, Shen, C, Miyamoto, T, Ahn, GY, Fei, W, Takeuchi, T, Shin, JM, Li, K, Kawaguchi, Y, Lee, YK, Wang, YF, Amano, K, Park, DJ, Yang, W, Tada, Y, Lau, YL, Yamaji, K, Zhu, Z, Shimizu, M, Atsumi, T, Suzuki, A, Sumida, T, Okada, Y, Matsuda, K, Matsuo, K, Kochi, Y, Yamamoto, K, Ohmura, K, Kim, TH, Yang, S, Yamamoto, T, Kim, BJ, Shen, N, Ikegawa, S, Lee, HS, Zhang, X, Terao, C, Cui, Y & Bae, SC 2022, 'Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study', Annals of the Rheumatic Diseases, vol. 81, no. 9, pp. 1273-1280. https://doi.org/10.1136/annrheumdis-2022-222345

TY - JOUR

T1 - Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

AU - Yin, Xianyong

AU - Kim, Kwangwoo

AU - Suetsugu, Hiroyuki

AU - Bang, So Young

AU - Wen, Leilei

AU - Koido, Masaru

AU - Ha, Eunji

AU - Liu, Lu

AU - Sakamoto, Yuma

AU - Jo, Sungsin

AU - Leng, Rui Xue

AU - Otomo, Nao

AU - Kwon, Young Chang

AU - Sheng, Yujun

AU - Sugano, Nobuhiko

AU - Hwang, Mi Yeong

AU - Li, Weiran

AU - Mukai, Masaya

AU - Yoon, Kyungheon

AU - Cai, Minglong

AU - Ishigaki, Kazuyoshi

AU - Chung, Won Tae

AU - Huang, He

AU - Takahashi, Daisuke

AU - Lee, Shin Seok

AU - Wang, Mengwei

AU - Karino, Kohei

AU - Shim, Seung Cheol

AU - Zheng, Xiaodong

AU - Miyamura, Tomoya

AU - Kang, Young Mo

AU - Ye, Dongqing

AU - Nakamura, Junichi

AU - Suh, Chang Hee

AU - Tang, Yuanjia

AU - Motomura, Goro

AU - Park, Yong Beom

AU - Ding, Huihua

AU - Kuroda, Takeshi

AU - Choe, Jung Yoon

AU - Li, Chengxu

AU - Niiro, Hiroaki

AU - Park, Youngho

AU - Shen, Changbing

AU - Miyamoto, Takeshi

AU - Ahn, Ga Young

AU - Fei, Wenmin

AU - Takeuchi, Tsutomu

AU - Shin, Jung Min

AU - Li, Keke

AU - Kawaguchi, Yasushi

AU - Lee, Yeon Kyung

AU - Wang, Yong Fei

AU - Amano, Koichi

AU - Park, Dae Jin

AU - Yang, Wanling

AU - Tada, Yoshifumi

AU - Lau, Yu Lung

AU - Yamaji, Ken

AU - Zhu, Zhengwei

AU - Shimizu, Masato

AU - Atsumi, Takashi

AU - Suzuki, Akari

AU - Sumida, Takayuki

AU - Okada, Yukinori

AU - Matsuda, Koichi

AU - Matsuo, Keitaro

AU - Kochi, Yuta

AU - Yamamoto, Kazuhiko

AU - Ohmura, Koichiro

AU - Kim, Tae Hwan

AU - Yang, Sen

AU - Yamamoto, Takuaki

AU - Kim, Bong Jo

AU - Shen, Nan

AU - Ikegawa, Shiro

AU - Lee, Hye Soon

AU - Zhang, Xuejun

AU - Terao, Chikashi

AU - Cui, Yong

AU - Bae, Sang Cheol

N1 - Funding Information: Contributors XY, KKim and HS contributed equally to this work, and either has the right to list himself first in bibliographic documents. SCB, YC, CT, XZhang, XY, KKim and HS conceived the study design. SCB, YC, XZhang, SY, KKim and CT acquainted the financial support. XY, KKim, HS, CT, YC and SCB wrote the manuscript. XY, KKim, HS, EH, XZheng, and YW conducted all of the analyses with the help of KT, NO, MK, KI and CTerao, KKim, SYB, LW, LL, RXL, YSheng, MYH, WL, KYoon, MC, HH, MW, YTang, ZZ, HD, CL, CS, WF, KL, BJK, HSL, SCB, SH, YSakamoto, NSugano, MM, DT, KKarino, TMiyamura, JN, GM, TKuroda, HN, TMiyamoto, TT, YKawaguchi, KA, YTada, KYamaji, MS, TA, AS, TSumida, YOkada, KMatsuda, KMatsuo, YKochi, TSeki, YTanaka, TKubo, RH, TYoshioka, MY, TKabata, YA, YOhta, TO, YN, AK, YY, KOhzono, KYamamoto, KOhmura, TYamamoto and SI generated genetic data. LL and HH contributed to ATAC-seq experiment. SJ and THK performed luciferase reporter assays and EMSAs. SYB, SJ, YCK, WTC, SSL, SCS, YMK, DY, CHS, YBP, JYC, YP, GYA, JMS, YKL, DJP, WY, THK, SY, BJK, NShen, HSL, XZhang, CT and SCB managed the cohort data. SCB, YC and CT had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: © 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85131254168&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85131254168&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2022-222345

DO - 10.1136/annrheumdis-2022-222345

M3 - Article

C2 - 35609976

AN - SCOPUS:85131254168

SN - 0003-4967

VL - 81

SP - 1273

EP - 1280

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 9

ER -

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

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