Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

Yong Fei Wang; Yan Zhang; Zhiming Lin; Huoru Zhang; Ting You Wang; Yujie Cao; David L. Morris; Yujun Sheng; Xianyong Yin; Shi Long Zhong; Xiaoqiong Gu; Yao Lei; Jing He; Qi Wu; Jiangshan Jane Shen; Jing Yang; Tai Hing Lam; Jia Huang Lin; Zhi Ming Mai; Mengbiao Guo; Yuanjia Tang; Yanhui Chen; Qin Song; Bo Ban; Chi Chiu Mok; Yong Cui; Liangjing Lu; Nan Shen; Pak C. Sham; Chak Sing Lau; David K. Smith; Timothy J. Vyse; Xuejun Zhang; Yu Lung Lau; Wanling Yang

doi:10.1038/s41467-021-21049-y

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

Yong Fei Wang, Yan Zhang, Zhiming Lin, Huoru Zhang, Ting You Wang, Yujie Cao, David L. Morris, Yujun Sheng, Xianyong Yin, Shi Long Zhong, Xiaoqiong Gu, Yao Lei, Jing He, Qi Wu, Jiangshan Jane Shen, Jing Yang, Tai Hing Lam, Jia Huang Lin, Zhi Ming Mai, Mengbiao GuoYuanjia Tang, Yanhui Chen, Qin Song, Bo Ban, Chi Chiu Mok, Yong Cui, Liangjing Lu, Nan Shen, Pak C. Sham, Chak Sing Lau, David K. Smith, Timothy J. Vyse, Xuejun Zhang, Yu Lung Lau, Wanling Yang

The Hormel Institute

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Abstract

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

Original language	English (US)
Article number	772
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21049-y
State	Published - Dec 1 2021

Bibliographical note

Funding Information:
We thank grant support from National Key Research and Development Program of China (2017YFC0909001), Hong Kong PhD fellowship scheme (HKPF), HKU Post-graduate Scholarships and the Edward and Yolanda Wong Fund for supporting post-graduate students who participated in this work. We also thank the Hong Kong Area of Excellence (AoE) NPC case-control study partially funded by the World Cancer Research Fund (WCRF) for sharing their GWAS data. Y.-F.W. thanks grant support from National Natural Science Foundation of China (Grant No. 81801636). Y.Z. thanks grant support from National Natural Science Foundation of China (Grant No. 81970450) and the Science and Technology Project of Guangzhou (Grant No. 201903010074). W.Y. and Y.L.L. thank Research Grant Council of Hong Kong for support on genetic studies of SLE (GRF 17146616,17106320).

Publisher Copyright:
© 2021, The Author(s).

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Wang, Y. F., Zhang, Y., Lin, Z., Zhang, H., Wang, T. Y., Cao, Y., Morris, D. L., Sheng, Y., Yin, X., Zhong, S. L., Gu, X., Lei, Y., He, J., Wu, Q., Shen, J. J., Yang, J., Lam, T. H., Lin, J. H., Mai, Z. M., ... Yang, W. (2021). Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nature communications, 12(1), [772]. https://doi.org/10.1038/s41467-021-21049-y

Wang, YF, Zhang, Y, Lin, Z, Zhang, H, Wang, TY, Cao, Y, Morris, DL, Sheng, Y, Yin, X, Zhong, SL, Gu, X, Lei, Y, He, J, Wu, Q, Shen, JJ, Yang, J, Lam, TH, Lin, JH, Mai, ZM, Guo, M, Tang, Y, Chen, Y, Song, Q, Ban, B, Mok, CC, Cui, Y, Lu, L, Shen, N, Sham, PC, Lau, CS, Smith, DK, Vyse, TJ, Zhang, X, Lau, YL & Yang, W 2021, 'Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups', Nature communications, vol. 12, no. 1, 772. https://doi.org/10.1038/s41467-021-21049-y

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title = "Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups",

abstract = "Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.",

author = "Wang, {Yong Fei} and Yan Zhang and Zhiming Lin and Huoru Zhang and Wang, {Ting You} and Yujie Cao and Morris, {David L.} and Yujun Sheng and Xianyong Yin and Zhong, {Shi Long} and Xiaoqiong Gu and Yao Lei and Jing He and Qi Wu and Shen, {Jiangshan Jane} and Jing Yang and Lam, {Tai Hing} and Lin, {Jia Huang} and Mai, {Zhi Ming} and Mengbiao Guo and Yuanjia Tang and Yanhui Chen and Qin Song and Bo Ban and Mok, {Chi Chiu} and Yong Cui and Liangjing Lu and Nan Shen and Sham, {Pak C.} and Lau, {Chak Sing} and Smith, {David K.} and Vyse, {Timothy J.} and Xuejun Zhang and Lau, {Yu Lung} and Wanling Yang",

note = "Funding Information: We thank grant support from National Key Research and Development Program of China (2017YFC0909001), Hong Kong PhD fellowship scheme (HKPF), HKU Post-graduate Scholarships and the Edward and Yolanda Wong Fund for supporting post-graduate students who participated in this work. We also thank the Hong Kong Area of Excellence (AoE) NPC case-control study partially funded by the World Cancer Research Fund (WCRF) for sharing their GWAS data. Y.-F.W. thanks grant support from National Natural Science Foundation of China (Grant No. 81801636). Y.Z. thanks grant support from National Natural Science Foundation of China (Grant No. 81970450) and the Science and Technology Project of Guangzhou (Grant No. 201903010074). W.Y. and Y.L.L. thank Research Grant Council of Hong Kong for support on genetic studies of SLE (GRF 17146616,17106320). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-21049-y",

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T1 - Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

AU - Wang, Yong Fei

AU - Zhang, Yan

AU - Lin, Zhiming

AU - Zhang, Huoru

AU - Wang, Ting You

AU - Cao, Yujie

AU - Morris, David L.

AU - Sheng, Yujun

AU - Yin, Xianyong

AU - Zhong, Shi Long

AU - Gu, Xiaoqiong

AU - Lei, Yao

AU - He, Jing

AU - Wu, Qi

AU - Shen, Jiangshan Jane

AU - Yang, Jing

AU - Lam, Tai Hing

AU - Lin, Jia Huang

AU - Mai, Zhi Ming

AU - Guo, Mengbiao

AU - Tang, Yuanjia

AU - Chen, Yanhui

AU - Song, Qin

AU - Ban, Bo

AU - Mok, Chi Chiu

AU - Cui, Yong

AU - Lu, Liangjing

AU - Shen, Nan

AU - Sham, Pak C.

AU - Lau, Chak Sing

AU - Smith, David K.

AU - Vyse, Timothy J.

AU - Zhang, Xuejun

AU - Lau, Yu Lung

AU - Yang, Wanling

N1 - Funding Information: We thank grant support from National Key Research and Development Program of China (2017YFC0909001), Hong Kong PhD fellowship scheme (HKPF), HKU Post-graduate Scholarships and the Edward and Yolanda Wong Fund for supporting post-graduate students who participated in this work. We also thank the Hong Kong Area of Excellence (AoE) NPC case-control study partially funded by the World Cancer Research Fund (WCRF) for sharing their GWAS data. Y.-F.W. thanks grant support from National Natural Science Foundation of China (Grant No. 81801636). Y.Z. thanks grant support from National Natural Science Foundation of China (Grant No. 81970450) and the Science and Technology Project of Guangzhou (Grant No. 201903010074). W.Y. and Y.L.L. thank Research Grant Council of Hong Kong for support on genetic studies of SLE (GRF 17146616,17106320). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

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N2 - Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

AB - Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

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Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

Abstract

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