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Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus

Nature Genetics volume 48, pages 940–946 (2016)Cite this article

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Abstract

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

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Figure 1: Comparison of Manhattan plots for the European and Chinese SLE GWASs.
Figure 2: Fine-mapping examples for STAT4, IRF7 and ELF1.
Figure 3: 3D enrichment plots depicting epigenetic modifications of ±50 bp overlapping all SNPs in the credibility sets for the 11 newly identified associated SNPs.
Figure 4: Box plots of GRS across the five major population groups.

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Gene Expression Omnibus

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Acknowledgements

P.T. is employed by the Biomedical Research Centre. L.C. was funded by the China Scholarship Council (201406380127). The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. T.J.V. was awarded funding to carry out genotyping and analysis from G. Koukis, an Arthritis Research UK Special Strategic Award, and the Wellcome Trust (grant 085492). T.J.V. was awarded funding by the MRC (L002604/1, “Functional genomics of SLE: a transancestral approach”). Y.C., X. Zhang, S.Y. and Y.S. acknowledge support from the Key Basic Research Program of China (2014CB541901, 2012CB722404 and 2011CB512103), the National Natural Science Foundation of China (81402590, 81371722, 81320108016 and 81171505), the Research Project of the Chinese Ministry of Education (213018A), the Program for New Century Excellent Talents in University (NCET-12-0600) and the Natural Science Fund of Anhui Province (1408085MKL27). W.Y. and Y.L.L. acknowledge support from the Research Grant Council of the Hong Kong Government (GRF HKU783813M, HKU 784611M, 17125114 and HKU 770411M). Y.Z. thanks the Health and Medical Research Fund (12133701) from the Food and Health Bureau, Hong Kong. We thank T. Raj and P. De Jager for contributing gene expression data (CD4+ T cells and CD14/16+ monocytes in Asian and European populations; available in the NCBI Gene Expression Omnibus under accession number GSE56035). We thank B. Fairfax and J. Knight for contributing gene expression data on NK cells, naive monocytes, LPS-stimulated monocytes (harvested after 2 h and 24 h), interferon and B cells. We thank S. Daffern for downloading the ChIP-seq data in contribution to the epigenetic analysis.

For the replication study in Europeans, samples were provided by the Swedish SLE Network (led by L.R.). Replication genotyping was performed by the SNP&SEQ Technology Platform in Uppsala, which is part of the Swedish National Genomics Infrastructure (NGI) hosted by Science for Life Laboratory. The controls for the European GWASs and replication were obtained from dbGaP accession phs000428.v1.p1 (a study sponsored by the National Institute on Aging (grants U01AG009740, RC2AG036495 and RC4AG039029) and conducted by the University of Michigan); melanoma study data under dbGaP accession phs000187.v1.p1; a blood clotting study (dbGaP accession phs000304.v1.p1); and prostate cancer study data under dbGaP accession phs000207.v1.

The French cases for the European replication study were provided by the PLUS study, funded by a grant from the French PHRC 2005 Ministère de la Santé (ClinicalTrials.gov: NCT00413361 to N.C-C.). Participants were F. Ackermann, Z. Amoura, B. Asli, L. Astudillo, O. Aumaître, C. Belizna, N. Belmatoug, O. Benveniste, A. Benyamine, H. Bezanahary, P. Blanco, O. Bletry, P. Bourgeois, B. Brihaye, P. Cacoub, E. Chatelus, J. Cohen-Bittan, R. Damade, E. Daugas, C. De-Gennes, J.-F. Delfraissy, A. Delluc, H. Desmurs-Clavel, P. Duhaut, A. Dupuy, I. Durieu, H.-K. Ea, O. Fain, D. Farge, C. Funck-Brentano, C. Frances, L. Galicier, F. Gandjbakhch, J. Gellen-Dautremer, B. Godeau, C. Goujard, C. Grandpeix, C. Grange, G. Guettrot, L. Guillevin, E. Hachulla, J.-R. Harle, J. Haroche, P. Hausfater, J.-S. Hulot, M. Jallouli, J. Jouquan, G. Kaplanski, H. Keshtmand, M. Khellaf, O. Lambotte, D. Launay, P. Lechat, D.L.T. Huong, V. Le-Guern, J.-E. Kahn, G. Leroux, H. Levesque, O. Lidove, N. Limal, F. Lioté, E. Liozon, L.Y. Kim, M. Mahevas, K. Mariampillai, X. Mariette, A. Mathian, K. Mazodier, M. Michel, N. Morel, L. Mouthon, J. Ninet, E. Oksenhendler, T. Papo, J.-L. Pellegrin, L. Perard, O. Peyr, A.-M. Piette, J.-C. Piette, V. Poindron, J. Pourrat, F. Roux, D. Saadoun, K. Sacre, S. Sahali, L. Sailler, B. Saint-Marcoux, F. Sarrot-Reynauld, Y. Schoindre, J. Sellam, D. Sène, J. Serratrice, P. Seve, J. Sibilia, C. Simon, A. Smail, C. Sordet, J. Stirnemann, S. Trad, J.-F. Viallard, E. Vidal, B. Wechsler, P.-J. Weiller, and N. Zahr.

Y.L.L. is thankful for generous donations from Shun Tak District Min Yuen Tong of Hong Kong that partially supported the SLE GWAS in Hong Kong. Y.L.L. and W.Y. thank the doctors who contributed SLE cases and colleagues in the LKS Faculty of Medicine, University of Hong Kong, who provided controls used in the GWASs.

Author information

Author notes

  1. David L Morris, Yujun Sheng, Yan Zhang and Timothy J Vyse: These authors contributed equally to this work.

  2. Wanling Yang, Yong Cui and Timothy J Vyse: These authors jointly supervised this work.

Authors and Affiliations

  1. Division of Genetics and Molecular Medicine, King's College London, London, UK

    David L Morris, Philip Tombleson, Lingyan Chen, Deborah S Cunninghame Graham, Amy L Roberts & Timothy J Vyse

  2. Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.,

    Yujun Sheng, Zhengwei Zhu, Xianbo Zuo, Leilei Wen, Chao Yang, Lu Liu, Lulu Yang, Feng Li, Yuanbo Huang, Xianyong Yin, Sen Yang, Xuejun Zhang & Yong Cui

  3. Key Laboratory of Dermatology, Ministry of Education, Anhui Medical University, Hefei, Anhui, China.,

    Yujun Sheng, Zhengwei Zhu, Xianbo Zuo, Leilei Wen, Chao Yang, Lu Liu, Lulu Yang, Feng Li, Yuanbo Huang, Xianyong Yin, Sen Yang, Xuejun Zhang & Yong Cui

  4. Department of Dermatology, China–Japan Friendship Hospital, Beijing, China

    Yujun Sheng & Yong Cui

  5. Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

    Yan Zhang, Yong-Fei Wang, Ruoyan Chen, Tingyou Wang, Yu Lung Lau & Wanling Yang

  6. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

    James Bentham

  7. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Lars Rönnblom

  8. Department of Internal Medicine 3, University of Erlangen–Nuremberg, Erlangen, Germany

    Barbara G Fürnrohr, Reinhard E Voll & Georg Schett

  9. Institute for Clinical Immunology, University of Erlangen–Nuremberg, Erlangen, Germany

    Barbara G Fürnrohr, Reinhard E Voll & Georg Schett

  10. Division of Genetic Epidemiology, Medical University Innsbruck, Innsbruck, Austria

    Barbara G Fürnrohr

  11. Division of Biological Chemistry, Medical University Innsbruck, Innsbruck, Austria

    Barbara G Fürnrohr

  12. Department of Rheumatology, University Hospital Freiburg, Freiburg, Germany

    Reinhard E Voll

  13. Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany

    Reinhard E Voll

  14. Centre for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany

    Reinhard E Voll

  15. AP–HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, Paris, France

    Nathalie Costedoat–Chalumeau

  16. Université Paris Descartes–Sorbonne Paris Cité, Paris, France

    Nathalie Costedoat–Chalumeau

  17. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

    Patrick M Gaffney

  18. The University of Hong Kong Shenzhen Hospital, Shenzhen, China

    Yu Lung Lau

  19. Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China

    Xuejun Zhang

  20. Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK

    Timothy J Vyse

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  1. David L Morris
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  2. Yujun Sheng
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Contributions

Y.-F.W., Z.Z. and P.T. contributed equally to this work. T.J.V., X. Zhang, Y.C., Y.L.L. and W.Y. supervised the study. Z.Z., L.W., C.Y., L.L., L.Y., F.L., Y.H., X.Y. and S.Y. performed sample selection and data management, undertook recruitment and collected phenotype data for the Anhui Chinese data. L.R., B.G.F., R.E.V., G.S., N.C.-C. and P.M.G. performed sample selection and data management, undertook recruitment and collected phenotype data for the European data. A.L.R. and Y.S. worked on genotyping of both Chinese and European replication studies. D.L.M., Y.S., Y.Z. and Y.-F.W. carried out statistical analysis of the GWAS data. D.L.M. and P.T. carried out the 1000 Genomes Project imputation in the European GWAS. Y.S., X. Zuo, R.C. and T.W. carried out the 1000 Genomes Project imputation in the Anhui and Hong Kong Chinese GWASs. D.L.M., P.T., Y.S., X. Zuo, Y.-F.W. and Y.Z. carried out statistical analysis for the meta-analysis of the 1000 Genomes Project imputed data. D.L.M., Y.S. and Y.Z. designed the replication studies' chips. B.G.F. and R.E.V. contributed data to the European replication cohort. D.L.M. and J.B. performed quality control on the European data for the replication study. D.L.M. analyzed European replication data. D.L.M., Y.S. and Y.Z. analyzed Anhui replication data. Y.-F.W. and D.L.M. designed and performed genetic risk score comparison between the populations. Y.-F.W. performed the LD score regression analysis. D.L.M. and L.C. carried out the eQTL analysis. D.L.M. and D.S.C.G. carried out the epigenetic analysis. D.L.M., T.J.V., D.S.C.G., X. Zhang, Y.C., Y.S. and W.Y. wrote the manuscript. All authors read and contributed to the manuscript.

Corresponding authors

Correspondence to Wanling Yang, Yong Cui or Timothy J Vyse.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 1–5, and Supplementary Notes 1–3 (PDF 8289 kb)

Supplementary Table 6

SNPs contained with the credibility sets for the newly discovered loci that also had peaks of chromatin marks (XLSX 38 kb)

Supplementary Table 7

The imputation quality information (XLSX 55 kb)

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Morris, D., Sheng, Y., Zhang, Y. et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet 48, 940–946 (2016). https://doi.org/10.1038/ng.3603

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